Sealant for tissue closure

Abstract

The invention relates to a biodegradable bilayer sealant for tissue closure. The sealant of the present invention consists of two layers having different compliance. The layer in direct contact with the tissue has high compliance. A second layer directly over the first sealant layer has low compliance, i.e., much harder sealant. The burst pressure of the double-layer sealant is increased relative to a single-layer elastic sealant or a single-layer rigid sealant. The improved sealant compositions herein provide a watertight seal, accessible to difficult-to-reach tear, applicable in dry or humid environments, low swell, and reparable for a range of cut or tear sizes. The bi-layer sealant is particularly useful for sutureless dura mater closure or as an adjuvant for sutured dura mater closure. Also provided herein are methods of making and using the biodegradable sealant compositions.

Description

Technical Field

[0001] The present invention relates to a biodegradable two-layer sealant composition for tissue closure and methods of using the same. Background Art

[0002] Sutures, patches, implants and sealants are used for tissue closure of wounds, lacerations or surgical incisions. Implantable and biodegradable hydrogel sealants typically exhibit a high degree of swelling, which may not be suitable for medical applications around or near sensitive organs and tissues, or for neurosurgery and orthopedic spine applications. In addition, there are few desirable sealant options for sealing sutured dural tissue, and there are currently no sealant options for sutureless dural closure.

[0003] Existing polyethylene glycol (PEG) based hydrogel sealants (e.g., DURASEAL, Integra Life Sciences, Princeton, NJ, and ADHERUS, Hyperbranch Medical Technology, Durham, NC) are used as adjuvants to obtain a watertight seal after primary dural tissue closure, such as after suturing the tissue. Such existing sealants are intentionally designed to result in a high cross-link density to reduce swelling, but may have undesirable brittle mechanics. The high cross-link density is a result of the inclusion of low molecular weight precursors such as trilysine (e.g., in DURASEAL) or substrates such as polyethyleneimine (e.g., in ADHERUS) with a high density of reactive sites.

[0004] There is a need for a tissue closure sealant that forms a watertight seal, can access hard-to-reach tears, is low swelling, flexible, and can repair a range of incision, wound, or tear sizes. Summary of the invention

[0005] Surprisingly and unexpectedly, the biodegradable and biocompatible double-layer sealant of the present invention replicates multiple mechanical properties and beneficial effects of adhesive patches. Provided herein is a biodegradable double-layer sealant comprising a first layer having an elastic composition and a second layer having a rigid composition. Due to tissue-like compliance, the elastic layer adheres and conforms to the tissue below, yet the rigid layer provides enhancement and limits the swelling of the elastic layer. The double-layer sealant combines the advantages of a separate elastic composition or a rigid composition. The elastic composition exhibits a high burst pressure, but has a high degree of swelling. The rigid composition is brittle and provides insufficient sealants, but the degree of swelling is low. As a double layer, the sealant exhibits both a high burst pressure and a low degree of swelling.

[0006] The double layer sealant can be used for difficult to access surgical applications, and medical procedures and surgical procedures involving sensitive organs and / or tissues, such as, but not limited to, neurosurgery, cranial surgery, spinal surgery, and orthopedic surgery. In addition, the double layer sealant herein can be used for primary and secondary tissue closure, for example as an adjunct to suture closure, and for medical procedures and applications where suture cannot be used or would not be desirable. The double layer sealant is particularly useful for sutureless primary dura closure in difficult to access suture situations.

[0007] In some embodiments, the elastic polymer composition of the double-layer sealant comprises a hydrogel. In some aspects, the elastic layer comprises a cross-linkable macromolecular polymer hydrogel. In some embodiments, the elastic polymer composition comprises a polyethylene glycol (PEG) hydrogel. In some aspects of the invention, the elastic polymer composition does not comprise a protein.

[0008] In other embodiments, the rigid polymer composition of the double-layer sealant comprises a hydrogel and at least one protein, peptide or polypeptide. In some aspects, the hydrogel in the rigid layer comprises a PEG hydrogel. In other aspects, the rigid layer comprises one or more reactive macromolecular polymers and at least one protein, peptide or polypeptide.

[0009] The terms "polypeptide", "peptide" or "protein" are used interchangeably herein and refer to polymers of amino acid residues. That is, the description of a polypeptide is equally applicable to the description of a peptide and to the description of a protein, and vice versa. The term is suitable for naturally occurring amino acid polymers and amino acid polymers in which one or more amino acid residues are non-naturally encoded amino acids. As used herein, the term encompasses amino acid chains of any length, including full-length proteins, in which the amino acid residues are linked by covalent peptide bonds. The polypeptide may also be modified in any of a variety of standard chemical ways (e.g., amino acids may be modified with protecting groups; carboxyl-terminated amino acids may be made into terminal amide groups; amino-terminated residues may be modified with groups, for example, to enhance lipophilicity; or polypeptides may be chemically glycosylated or otherwise modified to increase stability or in vivo half-life). Polypeptide modifications may include the connection of another structure (such as a cyclic compound or other molecule) to the polypeptide, and may also include polypeptides containing one or more amino acids (i.e., R or S; or L or D) of altered configuration.

[0010] The terms "elastic," "flexible," and "flexible" are used interchangeably herein.

[0011] In other aspects, the rigid polymer composition comprises a reactive PEG precursor and a protein. In some embodiments, the protein in the rigid layer is albumin, fibrinogen, ovalbumin, lactalbumin, an extracellular matrix protein, polylysine, collagen, gelatin, or a combination of two or more thereof.

[0012] In some aspects, the bi-layer sealant is sprayed or dripped onto the incision, tear or wound. In one aspect, two separate single-component delivery devices can be used to apply the bi-layer sealant to the tissue, or a two-component or dual-barrel delivery device can be used for sequential delivery of the first and second layers of the bi-layer sealant. In another aspect, two separate dual-barrel delivery devices can be used to prepare each of the elastic polymer composition and the rigid polymer composition, and then apply the elastic polymer composition and the rigid polymer composition to the tissue.

[0013] In another embodiment, a method for tissue closure is provided, wherein an elastic polymer composition is applied to the tissue in the form of a liquid solution. After the elastic polymer composition on the tissue is at least partially gelled or cured, a rigid polymer composition is applied to the elastic polymer composition in the form of a liquid solution, and a double-layer sealant is formed after the elastic polymer composition and the rigid polymer composition are cured.

[0014] A method for tissue closure is also provided, the method comprising: (a) applying a first layer on dura mater tissue, the first layer comprising a biodegradable elastic polymer composition comprising one or more reactive polyethylene glycols; (b) at least partially curing the first layer; and (c) applying a second layer on the surface of the first layer, wherein the second layer comprises a biodegradable rigid polymer composition comprising one or more reactive polyethylene glycols and a protein. In another aspect, a method of using the biodegradable double-layer sealant of the present invention for sutureless dura mater closure or as an adjunct to sutured dura mater closure is provided.

[0015] In another embodiment of the present invention, a kit is provided having a first storage container containing a biodegradable elastic polymer composition component and a second storage container containing a biodegradable rigid polymer composition component for application to tissue to form a double-layer sealant, wherein the rigid polymer composition has an elastic modulus that is approximately less than three times that of the elastic polymer composition.

[0016] In another embodiment, the present invention provides a method for preparing a double-layer sealant. In one aspect, a method for preparing a double-layer sealant for tissue closure is provided, the method comprising: (a) preparing an elastic polymer composition, comprising combining a first solution with a second solution, the first solution comprising a multi-arm PEG and a buffer solution, the second solution comprising a solution of multi-arm PEG in purified deionized water, and transferring the first solution and the second solution to separate 5 mL syringes in a first 10 mL double-barrel syringe device; (b) spraying about 1.5 mL to about 2 mL of the elastic polymer composition from the first 10 mL double-barrel syringe device onto the tissue to produce a thickness of about 1.5 mm and partially curing the elastic polymer composition; (c) preparing a rigid polymer composition, comprising: combining a third solution with a fourth solution. The third solution is a solution of albumin in sodium carbonate buffer, and the fourth solution is a solution of multi-arm PEG in purified deionized water; (d) the third solution and the fourth solution are each transferred to a separate 5 mL syringe in a second 10 mL double-barrel syringe device, and (e) about 0.25 mL to about 0.5 mL of the rigid polymer composition is sprayed from the second 10 mL double-barrel syringe device onto the surface and edge of the partially cured elastic polymer composition to produce a thickness of 0.5 mm and allow the double-layer sealant to cure.

[0017] Provided herein are aspects and properties of an elastomeric polymer composition and a rigid polymer composition that result in a novel dual-layer sealant.

[0018] In some embodiments, the digits of the amount of the representative components, characteristics such as molecular weight, reaction conditions, elastic modulus, elongation at break, swelling percentage, concentration and results etc. used to describe and claim certain embodiments of the present disclosure should be understood to be modified by the term "about" in some cases. One of ordinary skill in the art will understand the meaning of the term "about" in the context of the value modified by it. In some embodiments, the term "about" is used to indicate that the value includes the standard deviation of the mean value of the device or method for determining the value. In some embodiments, the numerical parameter is an approximation, which can vary according to the desired characteristics sought to be obtained by a specific embodiment. In some embodiments, the numerical parameter should be interpreted according to the number of reported significant figures and by applying common rounding techniques.

[0019] As used herein, the terms "comprises", "comprising", "having" and their grammatical variations should be considered to specify the stated features, integers, steps or components, but do not exclude the addition of one or more further features, integers, steps, components or groups thereof. These terms encompass the terms "consisting of" and "consisting essentially of". Furthermore, as used herein, the indefinite articles "a" and "an" mean "at least one" or "one or more", unless the context clearly indicates otherwise.

[0020] These and other aspects and advantages of the present invention will become more apparent from the following description and accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 Depicted is a cross-section of a two-layer sealant composition of the present invention comprising an elastic polymer composition 10 applied to the dura mater and a rigid polymer composition 12 applied over the elastic polymer composition.

[0022] Figure 2A Graph showing burst pressure (mmHg) testing of a two-layer sealant composition of the present invention for various elastomeric layer to rigid layer ratios, as well as a first control composition having only an elastomeric composition and a second control composition having only a rigid composition.

[0023] Figure 2B is a graph showing the normal distribution of burst pressure at various percentage thicknesses of the elastic (flexible hydrogel) layer of the bilayer composition of the present invention.

[0024] Figure 3 Graph showing the percent swelling of a two-layer sealant composition of the present invention having various thickness ratios of the elastic layer and the rigid layer composition, as well as a first control having only the elastic layer composition and a second control having only the rigid layer composition. DETAILED DESCRIPTION

[0025] The present invention relates to a double layer sealant that replicates multiple mechanical properties and benefits of an adhesive patch in a liquid sealant. The biodegradable and biocompatible double layer sealant compositions provided herein can be used in difficult to access surgical applications. The double layer sealant adheres to tissue and closes tissue tears or incisions but does not suture or act as an aid in suturing tissue. Surprisingly, the double layer sealant not only provides a durable seal, but also exhibits a low degree of swelling compared to the use of a single layer sealant composition alone. The present invention provides a double layer sealant comprising an elastic layer and a rigid layer to obtain a desired new high burst pressure low swelling sealant suitable for sutureless tissue closure.

[0026] The dura mater, dura mater or dura mater tissue is the connective tissue that protects the brain and spinal cord. It is the outermost layer of the meninges. The dura mater tissue is subject to tearing and dehydration. Alternatively, the dura mater is sometimes deliberately cut and ruptured to perform subdural surgery. Both dura mater tears and intentional incisions can lead to undesirable cerebrospinal fluid leakage, which can lead to complications such as infection and meningitis.

[0027] The bi-layer sealants of the present invention form a watertight seal, can be used to repair hard-to-reach tears, are low swelling, and can repair a range of dural incision or tear sizes. The sealant compositions disclosed herein provide the reliability desired by surgeons, particularly in tissues or areas where suturing is difficult or impossible. In addition, the bi-layer sealants can reduce the duration of operating room procedures by eliminating the need to suture the dura, thereby reducing surgical time. The bi-layer sealant compositions simplify dural closure procedures, reduce hospital stays, and minimize postoperative complications.

[0028] High burst pressure and low swelling sealants are needed for sutured or sutureless tissue closure. Currently available PEG-based hydrogel sealants include low molecular weight precursors such as trilysine (e.g., DURASEAL) or substrates such as polyethyleneimine (e.g., ADHERUS) to achieve high crosslink density for low swelling, but are limited by brittle mechanics. Such brittle mechanics can lead to undesirable sealant failure when exposed to pressure spikes, for example, when a patient sneezes, coughs, lifts a heavy object, or is subjected to a sudden impact.

[0029] The sealant of the present invention is composed of two layers with different compliances, which facilitates primary dura mater closure. The elastic polymer composition in direct contact with the tissue is flexible and has a high compliance similar to the dura mater tissue. The polymer composition directly above the first sealant layer has a higher hardness.

[0030] Surprisingly, the biodegradable sealants provided herein have advantageously high burst strengths in addition to strong tissue adhesion. The burst pressure of the double-layer sealant is increased relative to a single-layer elastic sealant or a single-layer rigid sealant. The elastic layer allows the double-layer sealant to mimic the natural mechanism of the dura mater and conform well to the tissue. On the other hand, the rigid layer provides a degree of strain or elongation limitation to the double-layer sealant. This limitation is advantageous because it prevents the double-layer sealant from straining beyond its extension upon failure.

[0031] The structural stiffness of the composition is essentially the weighted average of the elastic modulus (E) and the thickness (T), i.e., the structural stiffness ∝E 弹性 T 弹性 +E 刚性 T 刚性. Thus, the structural stiffness of the sealant bilayer can be adjusted by varying the thickness of each layer. Thus, when the total thickness is held constant, increasing the thickness of the elastic layer will reduce the overall stiffness, and increasing the thickness of the rigid layer will increase the overall stiffness. Generally, increased elasticity is associated with increased swelling. The composite swelling of the bilayer sealant herein can be reduced relative to a single layer of elastic sealant composition. Swelling equilibrium occurs when the osmotic pressure caused by the influx of fluid is balanced by the resulting pressure generated by the strain in the polymer molecules. The inclusion of a rigid layer increases the resistance to the osmotic pressure, resulting in a reduced degree of swelling at equilibrium.

[0032] In one embodiment, a method for tissue closure is provided, wherein a first elastic polymer composition is applied to the tissue in the form of a liquid solution. After the first elastic polymer composition on the tissue is at least partially gelled or cured, a rigid polymer composition is applied to the elastic polymer composition in liquid form.

[0033] A method for dural tissue closure is provided, the method comprising: (a) applying a first layer on the dural tissue, the first layer comprising a biodegradable elastic polymer composition; (b) at least partially curing the first layer; and (c) applying a second layer over the entire surface of the elastic polymer composition, wherein the second layer comprises a biodegradable rigid polymer composition.

[0034] In one aspect, a method for dural tissue closure is provided, the method comprising: (a) applying a first layer on the dural tissue, the first layer comprising a biodegradable elastic polymer composition comprising polyethylene glycol; (b) at least partially curing the first layer; and (c) applying a second layer over the entire surface of the elastic polymer composition, wherein the second layer comprises a biodegradable rigid polymer composition comprising polyethylene glycol and a protein.

[0035] In some embodiments, the double-layer sealant composition provided herein is formed in situ. In some aspects, the double-layer sealant composition is sprayed or dripped onto a dura defect or incision. In other aspects, an elastic liquid sealant composition and a rigid liquid sealant composition are applied with a syringe or other applicator. The device suitable for applying the sealant of the present invention can apply the double-layer sealant to the dura tissue, can apply the double-layer sealant evenly to the inaccessible tissue, prevent the liquid composition from leaking by providing a closed volume for accommodating the fluid, and has a short fluid path, thereby eliminating and / or minimizing the risk of entrance obstruction caused by the cross-linking of the fluid. Such a device enables a user (such as a surgeon or other practitioner) to evenly apply the double-layer sealant composition of the present invention, but the substance does not leak from the device, and eliminates or reduces the risk of the sealant composition solidifying or cross-linking before it is applied to the tissue. The preferred device enables the application of a desired volume of sealant, thereby producing a seal of desired height, width and length, to achieve excellent sealing and prevent cerebrospinal fluid from tearing or incision leakage from the dura.

[0036] A variety of devices can be used to apply the first and second compositions. For example, two separate single component delivery devices, or a two-component or dual cartridge delivery device can be used for sequential delivery of the first and second layers of a two-layer sealant.

[0037] As used herein, the term "curing" or "curable" in relation to a fluid composition refers to a composition that can undergo an interaction between its components resulting in an increase in the viscosity of the composition. Such interactions include polymerization and / or cross-linking of the components with or without the use of an activator such as a catalyst or a physical activator such as heat, radiation, e.g., ultraviolet radiation, electron beam, or a combination thereof.

[0038] After applying the elastic polymer composition on the tissue, the mixing of the elastic polymer composition components and contact with the protein / amine at the tissue interface initiates the curing of the elastic sealant and the formation of covalent bonds at the tissue interface. The partial gel time of the elastic layer is about 30 seconds to 60 seconds, after which 0.25 mL to 0.5 mL of the rigid polymer composition is applied by spraying or dripping, thereby covering the entire surface and edges of the elastic layer to produce a thickness of 0.5 mm. The mixing of the rigid polymer composition components and contact with the elastic sealant and tissue edges will initiate the curing of the rigid sealant; thereby forming covalent bonds at the elastic sealant surface and the tissue-edge interface.

[0039] The elastic layer is swellable, flexible, and has the desired swelling properties. Preferably, the elastic polymer composition is an swellable hydrogel, such as a PEG hydrogel or other macromolecular hydrogel. Biodegradable hydrogels that degrade via hydrolysis are preferably used in the sealant compositions described herein. In some embodiments, the layers of the double-layer sealant are connected by functional groups and / or joints. In some embodiments, the elastic polymer composition is a hydrogel, and the rigid polymer composition comprises a cross-linking agent and one or more proteins. In some preferred embodiments, the hydrogel of the elastic polymer composition is a PEG hydrogel or other macromolecular hydrogel, and the rigid polymer composition comprises PEG or other macromolecular hydrogel and albumin or other suitable proteins. In some aspects, the two layers are composed of compatible or mutually reactive chemicals that allow covalent bonding between the two layers. For example, the ester on the PEG molecule in the elastic polymer composition forms an amide bond with the protein in the rigid layer.

[0040] PEG suitable for elastic layer is multi-arm PEG, such as 2-arm, 3-arm, 4-arm, 6-arm or 8-arm multi-arm PEG. For example, multi-arm PEG is commercially available from JenKem Technologies or NOF Corporation. In a preferred embodiment, multi-arm PEG has a molecular weight of about 2 kDa to about 40 kDa. In some embodiments, PEG suitable for elastic layer is multi-arm PEG with reactive functional groups at each end of the arm, such as N-hydroxysuccinimide (NHS) ester groups. At a pH of about 7 to about 10, the NHS ester groups of PEG in the elastic layer and the primary amines of the protein in the rigid layer form a stable conjugate, i.e., an amide bond. Examples of PEG used in the elastic layer are 4-arm-PEG-succinimidyl glutarate (SG), 4-arm-PEG-succinimidyl valerate, 4-arm-PEG-succinimidyl carbonate, 4-arm-PEG-succinimidyl succinate, 4-arm-PEG-succinimidyl butyrate, 4-arm-PEG-succinimidyl succinamide, 4-arm-PEG-succinimidyl propionate, 4-arm-PEG-sulfosuccinimidyl glutarate (SG), 4-arm-PEG- PEG-sulfosuccinimidyl valerate, 4-arm-PEG-sulfosuccinimidyl carbonate, 4-arm-PEG-succinimidyl carboxymethyl ester, 4-arm-PEG-sulfosuccinimidyl succinate, 4-arm-PEG-sulfosuccinimidyl butyrate, 4-arm-PEG-sulfosuccinimidyl succinamide, 4-arm-PEG-sulfosuccinimidyl propionate, and 4-arm-PEG-isocyanate, 4-arm-PEG-imidate and 4-arm-PEG-maleimide. Other examples include linear 6-arm-PEG of the above chemistries.

[0041] In some embodiments, the elastic layer is biosynthetic, for example, the elastic layer may comprise PEG-amine.

[0042] In another aspect, thiols are suitable for use in the rigid layer and reacted with PEG-NHS ester and PEG-maleimide which are suitable for use in the elastic layer.

[0043] In some embodiments, the elastic layer comprises PEG at a total concentration of about 80 mg / mL to about 200 mg / mL. In a preferred embodiment, the total concentration of PEG is about 124 mg / mL. Examples of preferred PEGs for the elastic layer are 4-arm-PEG-succinimidyl glutarate, MW 20,000 (4-arm-PEG-SG-20k) (62 mg / mL), available from JenKem Technologies or NOF Corporation, and 4-arm-PEG-amine, MW 12,000 (4-arm-PEG-NH2 12K) (62 mg / mL), available from JenKem Technologies or NOF Corporation.

[0044] In some embodiments, the rigid layer is biosynthetic or completely biological, such as fibrin, fibrinogen, collagen, and / or cellulose preparations.

[0045] The albumin used in the rigid polymer composition of the double-layer sealant herein is bovine serum albumin (BSA), human serum albumin (HSA), recombinant human albumin, synthetic albumin, and albumin variants. Bovine serum albumin (BSA) is commercially available from a variety of sources, for example, United States Pharmacopeia (USP) reference standard bovine serum albumin is available from Sigma-Aldrich (St. Louis, Missouri). Recombinant human albumin, USP is commercially available from a variety of sources, for example, Sigma-Aldrich (St. Louis, Missouri).

[0046] In some embodiments, the rigid layer comprises albumin at a concentration of about 50 mg / mL to about 300 mg / mL. In a preferred embodiment, the concentration of albumin in the rigid layer composition is 150 mg / mL. In another embodiment, the rigid polymer composition comprises albumin or other suitable protein, and PEG or other macromolecules.

[0047] Other proteins suitable for use in the rigid polymer composition include fibrin, ovalbumin, whey protein, collagen, gelatin, extracellular matrix proteins, and polylysine.

[0048] Other macromolecular cross-linking agents useful in the hydrogels of the bilayer sealants provided herein include functionalized polyethylene glycols.

[0049] In some aspects, the elastic polymer composition and the rigid polymer composition comprise additional ingredients, such as carbonate buffer, phosphate buffer, and phosphate buffered saline. In other aspects, the polymer composition herein comprises a buffer to adjust the pH of the composition to about pH 7 to about pH 10.

[0050] In some embodiments, the total thickness of the double-layer sealant is about 1.5 mm to about 5.0 mm. The central area of ​​the double-layer sealant application site generally has a slightly thicker application than the edges of the double-layer sealant. The elastic layer is applied to the dura defect by spraying or dripping, wherein the tissue is reapproximated with a thickness of 0.9 mm to about 1.95 mm. In some embodiments, the thickness of the double-layer sealant applied by spraying is about 1.5 mm to about 2.6 mm. In other embodiments, the thickness of the double-layer sealant applied by dripping is about 3.0 mm to about 5.0 mm. For example, for a total double-layer sealant thickness of 2.2 mm applied to the dura by spraying at a 1:1 ratio, it can be 1.1 mm elastic layer to 1.1 mm rigid layer. In another aspect, by spraying a total double-layer thickness of 2.2 mm applied at a 3:1 ratio, it can be 1.65 mm elastic layer to 0.55 mm rigid layer.

[0051] The gel time of the elastic layer is about 30 seconds to 60 seconds. The rigid layer can be applied about 1 minute to 2 minutes after the elastic layer. The rigid layer is then applied by spraying or dripping on the surface of the elastic layer at a thickness of about 0.5 mm to about 1.3 mm. The preferred range of the average diameter ratio of the double-layer sealant polymer composition provided herein is about 1:1 elastic layer to rigid layer to about 3:1 elastic layer to rigid layer.

[0052] In some embodiments, bi-layer sealant degradation occurs in less than about 8 weeks after application.

[0053] In another aspect, the biodegradable sealant is characterized by a desired burst pressure of at least 75 mmHg. For a 3:1 elastic:rigid ratio bi-layer sealant, the average burst pressure was about 85.8 mmHg, ranging from about 53.7 mmHg to about 103.9 mmHg. For a 1:1 elastic:rigid ratio bi-layer sealant, the average burst pressure was 110.5 mmHg, ranging from about 32.7 mmHg to about 141.3 mmHg. Existing dural sealants DURASEAL and ADHERUS are used as adjuncts after initial dural closure and have average burst pressures of about 15.9 mmHg and 25.9 mmHg, respectively.

[0054] In another aspect, the elastic modulus (Young's modulus) of the elastic layer in the cured state is from about 19.2 kPa to about 24.2 kPa. In one embodiment, the elastic polymer composition is characterized by an elongation at break of at least about 300%. In another embodiment, the rigid polymer composition layer is characterized by an elastic modulus less than that of the elastic layer, such as from about 33.4 kPa to about 47.6 kPa and / or an elongation at break of from about 40% to about 110%.

[0055] In a preferred embodiment, the elastic layer is characterized by an ultimate tensile stress of about 40 kPa to about 80 kPa and an elongation at break of about 245% to 508%.

[0056] In one aspect, the biodegradable dual-layer sealant is characterized by a swelling percentage that is at least about 1.4 times lower than the swelling percentage of a single layer of the elastomeric polymer composition having the same thickness, as measured in an aqueous medium such as phosphate buffered saline (PBS) after 6 days at 37° C. In another aspect, the biodegradable sealant is characterized by a swelling percentage of about 70% to about 110%, as measured in an aqueous medium after 6 days at 37° C.

[0057] In another embodiment, provided herein is a method for preparing a double-layer sealant. In one aspect, provided is a method for preparing a double-layer sealant, the method comprising: (a) preparing an elastic polymer composition, comprising combining a first solution comprising 124 mg / mL 4-arm-PEG-NH2-20K in about 200 mM N-cyclohexyl-2-aminoethanesulfonic acid (CHES) buffer at a pH of about 9.35 and a second solution comprising 124 mg / mL (a) preparing a solution of 4-arm-PEG-succinimidyl glutarate in purified deionized water, and transferring the first solution and the second solution into separate 5 mL syringes in a first 10 mL double barrel syringe device; (b) spraying about 1.5 mL to about 2 mL of the elastic polymer composition from the first 10 mL double barrel syringe device onto the dura mater tissue to produce a thickness of about 1.5 mm and partially curing the elastic polymer composition; (c) preparing a rigid polymer composition comprising combining a third solution of 300 mg / mL bovine serum albumin in about 200 mM sodium carbonate buffer at a pH of about 9.0 with a fourth solution of about 200 mg / mL bovine serum albumin in about 200 mM sodium carbonate buffer at a pH of about 9.0. (d) transferring the third solution and the fourth solution into separate 5 mL syringes in a second 10 mL double-barrel syringe apparatus, and (e) spraying from about 0.25 mL to about 0.5 mL of the rigid polymer composition from the second 10 mL double-barrel syringe apparatus onto the surface and edges of the partially cured elastic polymer composition to produce a thickness of 0.5 mm and allowing the double-layer sealant to cure.

[0058] In another aspect, the elastic layer is configured to face the tissue site and adhere to the tissue site. The swelling percentage of the dual-layer sealant of the present invention is particularly advantageous for sealing dura tissue compared to currently available dura sealants such as DURASEAL, which have a swelling percentage of about 200% under comparable conditions.

[0059] In one aspect, the bilayer sealants of the present invention provide an antimicrobial impermeable barrier. In addition, the elastic layer of the bilayer sealants provided herein adheres to the dura tissue, but advantageously does not adhere to other nearby tissues or organs.

[0060] In another embodiment of the present invention, a kit for applying an elastic polymer composition and a rigid polymer composition to a tissue to form a double-layer sealant for tissue closure is provided, wherein the kit includes a first storage container containing a first solution and a second storage container containing a second solution for preparing a biodegradable elastic polymer composition component; and a third storage container containing a third solution and a fourth storage container containing a fourth solution for preparing a biodegradable rigid polymer composition component. In some aspects, the elastic polymer composition component of the kit comprises polyethylene glycol, and the rigid polymer composition component of the kit comprises polyethylene glycol and a protein; and wherein after applying the rigid polymer composition to the surface of the elastic polymer composition and curing the composition, the rigid polymer composition has an elastic modulus of about less than three times that of the elastic polymer composition. The kit may optionally include four 5mL syringes and two 10mL double-barrel syringe devices.

[0061] In summary, the present invention encompasses, inter alia, the following embodiments:

[0062] Embodiment 1 of the present disclosure relates to a biodegradable double-layer sealant for tissue closure, the double-layer sealant comprising a first layer comprising an elastic polymer composition and a second layer comprising a rigid polymer composition, wherein a layer thickness ratio of the elastic polymer composition to the rigid polymer composition is about 1:1 to about 3:1, respectively.

[0063] Embodiment 2: The two-layer sealant according to Embodiment 1, wherein the elastic polymer composition and the rigid polymer composition are connected by a covalent bond.

[0064] Embodiment 3: The double-layer sealant according to Embodiment 1 or 2, wherein the elastic polymer composition and / or the rigid polymer composition is a hydrogel.

[0065] Embodiment 4: The two-layer sealant according to Embodiment 3, wherein the hydrogel comprises mutually reactive polyethylene glycol.

[0066] Embodiment 5: The double-layer sealant according to Embodiment 4, wherein the polyethylene glycol is a multi-arm polyethylene glycol.

[0067] Embodiment 6: The two-layer sealant according to any one of Embodiments 1 to 5, wherein the rigid polymer composition further comprises a protein or a peptide and a cross-linking agent.

[0068] Embodiment 7: The double-layer sealant according to Embodiment 6, wherein the protein is albumin.

[0069] Embodiment 8: The double-layer sealant according to embodiment 7, wherein the albumin is selected from the group consisting of bovine serum albumin, human serum albumin, recombinant human albumin, albumin variants and synthetic albumin.

[0070] Embodiment 9: The double-layer sealant according to embodiment 7, wherein the protein is selected from the group consisting of fibronectin, ovalbumin, lactalbumin, extracellular matrix protein, polylysine, and combinations of two or more thereof.

[0071] Embodiment 10: The double layer sealant of any one of Embodiments 1 to 9, wherein the double layer sealant has a burst pressure of at least about 80 mmHg.

[0072] Embodiment 11: The two-layer sealant of any one of Embodiments 1 to 10, wherein the elastic polymer composition has an elastic modulus of about 19 kPa to about 24 kPa.

[0073] Embodiment 12: The two-layer sealant of any one of Embodiments 1 to 11, wherein the elastomeric polymer composition has an elongation at break of at least about 245%.

[0074] Embodiment 13: The two-layer sealant of any one of Embodiments 1 to 12, wherein the rigid polymer composition has an elastic modulus less than three times that of the elastic polymer composition and an elongation at break of about 100%.

[0075] Embodiment 14: A double-layer sealant according to any one of Embodiments 1 to 13, wherein the sealant has a swelling percentage in an aqueous medium after 6 days at 37°C that is at least about 1.4 times lower than the swelling percentage of an elastic polymer composition having the same thickness in an aqueous medium after 6 days at 37°C.

[0076] Embodiment 15: The two-layer sealant of any one of Embodiments 1 to 14, wherein the sealant has a swelling percentage of about 70% to about 110% as measured in an aqueous medium after 6 days at 37°C.

[0077] Embodiment 16 relates to a method for tissue closure, for example by preparing a double-layer sealant, the method comprising: (a) applying a first layer on the tissue, the first layer comprising a biodegradable elastic polymer composition, the elastic polymer composition comprising multi-arm polyethylene glycol; (b) at least partially curing the first layer; and (c) applying a second layer on the surface of the elastic polymer composition, wherein the second layer comprises a biodegradable rigid polymer composition, the rigid polymer composition comprising multi-arm polyethylene glycol and a protein or peptide.

[0078] Embodiment 17: A method for tissue closure according to embodiment 16, wherein the multi-arm polyethylene glycol is selected from 4-arm-PEG-amine, 4-arm-PEG-N-hydroxysuccinimide, 6-arm-PEG-N-hydroxysuccinimide, 4-arm-PEG-succinimidyl glutarate, 4-arm-PEG-succinimidyl carbonate, 4-arm-PEG-acrylate, 4-arm-PEG-succinimidyl valerate, 4-arm-PEG-succinimidyl succinate, 4-arm-PEG-succinimidyl butyrate, 4-arm-PEG-succinimidyl succinamide, 4-arm-PEG-succinimidyl propionate. Ester, 4-arm-PEG-sulfosuccinimidyl glutarate (SG), 4-arm-PEG-sulfosuccinimidyl valerate, 4-arm-PEG-sulfosuccinimidyl carbonate, 4-arm-PEG-succinimidyl carboxymethyl ester, 4-arm-PEG-sulfosuccinimidyl succinate, 4-arm-PEG-sulfosuccinimidyl butyrate, 4-arm-PEG-sulfosuccinimidyl succinamide, 4-arm-PEG-sulfosuccinimidyl propionate, and 4-arm-PEG-isocyanate, 4-arm-PEG-imidate, and 4-arm-PEG-maleimide, and combinations of two or more thereof.

[0079] Embodiment 18: The method for tissue closure according to embodiment 16 or 17, wherein the protein is selected from the group consisting of albumin, fibronectin, ovalbumin, lactalbumin, extracellular matrix protein, polylysine, and a combination of two or more thereof.

[0080] Embodiment 19: A method for tissue closure according to any one of Embodiments 16 to 18, wherein the layer thickness ratio of the elastic polymer composition to the rigid polymer composition is about 1:1 to about 3:1; the elastic polymer composition has an elastic modulus of about 19 kPa to about 24 kPa; and the rigid polymer composition has an elastic modulus of about less than three times that of the elastic polymer composition.

[0081] Embodiment 20 relates to a kit for preparing a biodegradable double-layer sealant for closing tissue, the kit comprising a first storage container containing a first solution for preparing a biodegradable elastic polymer composition component and a second storage container containing a second solution, the first solution comprising a solution of multi-arm PEG in cyclohexyl-2-aminoethanesulfonic acid (CHES) buffer, and the second solution comprising a solution of multi-arm PEG in purified deionized water; a third storage container containing a third solution for preparing a biodegradable rigid polymer composition component and a fourth storage container containing a fourth solution, the third solution comprising a solution of a protein or peptide in sodium carbonate buffer, and the fourth solution comprising a solution of multi-arm PEG in purified deionized water; and wherein after applying the rigid polymer composition to the surface of the elastic polymer composition and curing the elastic polymer composition and the rigid polymer composition, the rigid polymer composition has an elastic modulus approximately less than three times that of the elastic polymer composition.

[0082] Embodiment 21 relates to a method for preparing a double-layer sealant for tissue closure, the method comprising: (a) preparing an elastic polymer composition comprising combining a first solution comprising about 80 mg / mL to about 200 mg / mL of PEG-NH2-20K in about 200 mM N-cyclohexyl-2-aminoethanesulfonic acid (CHES) buffer at a pH of about 9.35 with a second solution comprising about 80 mg / mL to about 200 mg / mL of 4-arm-PEG-succinimidyl glutarate in purified deionized water, and transferring the first solution and the second solution to separate 5 mL syringes in a first 10 mL double-barrel syringe device; (b) spraying about 1.5 mL to about 2 mL of the elastic polymer composition from the first 10 mL double-barrel syringe device onto tissue to produce a thickness of about 1.5 mm and partially curing the elastic polymer composition; (c) preparing a rigid polymer composition comprising combining a third solution of about 50 mM PEG-NH2-20K in about 200 mM N-cyclohexyl-2-aminoethanesulfonic acid (CHES) buffer at a pH of about 9.35 with a fourth solution. (e) spraying from about 0.25 mL to about 0.5 mL of the rigid polymer composition from the second 10 mL double barrel syringe onto the surface and edges of the partially cured elastic polymer composition to produce a thickness of about 0.5 mm and allowing the double layer sealant to cure.

[0083] Additional details regarding the dual layer sealants of the present invention are provided in the following non-limiting examples.

[0084] Example

[0085] The following materials were obtained for the preparation and testing of the bilayer sealant: 4-arm-PEG-amine, molecular weight 20,000 (4-arm-PEG-NH2-20K), purchased from JenKem Technologies; 4-arm-PEG-succinimidyl glutarate, molecular weight 20,000 (4-arm-PEG-SG-20K), purchased from JenKem Technologies; bovine serum albumin purchased from Sigma, sodium carbonate purchased from Sigma; and N-cyclohexyl-2-aminoethanesulfonic acid (CHES) purchased from Sigma. The testing equipment included a pressure gauge (IP-073), a timer (EC-203), a caliper (ID-0164), and a standard syringe pump.

[0086] Example 1

[0087] Preparation of elastic polymer composition for double-layer sealant

[0088] To prepare the elastomeric polymer composition for the double-layer sealant, first prepare a solution of 124 mg / mL 4-arm-PEG-amine, molecular weight 20,000 (4-arm-PEG-NH2-20K) in 200 mM N-cyclohexyl-2-aminoethanesulfonic acid (CHES) buffer at a pH of about 9.35. Next, prepare a solution of 124 mg / mL 4-arm-PEG-succinimidyl glutarate, molecular weight 20,000 (4-arm-PEG-SG-20K) in purified deionized (DI) water. Each solution is then transferred to a separate 5 mL Luer-Lok syringe to set up a 10 mL double barrel syringe apparatus with a mixing tip in preparation for immediate extrusion. The final concentration of the mixed elastomeric polymer composition is 62 mg / mL 4-arm-PEG-NHS-20K, 100 mM CHES, and 62 mg / mL 4-arm-PEG-SG-20K.

[0089] Example 2

[0090] Preparation of rigid polymer compositions for dual-layer sealants

[0091] To prepare the rigid polymer composition of the double-layer sealant, first prepare a solution of 300 mg / mL bovine serum albumin, molecular weight about 66 kDa (BSA) in 200 mM sodium carbonate buffer at a pH of about 9.0. Next, prepare a solution of 200 mg / mL 4-ARM-PEG-succinimidyl glutarate, molecular weight 10,000 (4-ARM-PEG-SG-10K) in purified deionized (DI) water. Each solution is then transferred to a separate 5 mL Luer-Lok syringe to set up a 10 mL double barrel syringe apparatus with a mixing tip, ready for immediate extrusion. The final concentrations in the mixed sealant are 150 mg / mL BSA, 100 mM sodium carbonate, and 100 mg / mL 4-ARM-PEG-SG-10K.

[0092] Example 3

[0093] Applying a first elastic polymer composition and a second rigid polymer composition to form a double layer sealant .

[0094] After preparing the elastic polymer composition and the rigid polymer composition in a 10 mL double barrel syringe device, the former is first extruded from the double barrel syringe. On the re-approximated 15 mm linear dura / tissue tear, about 1.5 mL to about 2 mL of the elastic sealant is applied via a spray or drip mixing tip to produce a thickness of about 1.5 mm. The mixing of the components and contact with the protein / amine at the tissue interface will trigger the curing of the elastic sealant; covalent bonds are formed at the tissue interface. The partial gel time of this elastic layer is about 30 seconds to 60 seconds, after which the rigid sealant can be applied. Then 0.25 mL to 0.5 mL of the rigid layer is applied by spraying or dripping, covering the entire surface and edges of the elastic layer to produce a thickness of 0.5 mm. The mixing of the rigid sealant components and contact with the protein / amine on the elastic sealant and tissue edges will trigger the curing of the rigid sealant; thereby forming covalent bonds at the elastic sealant surface and tissue-edge interface. The average diameter ratio of the double-layer sealant polymer composition after curing is about 3:1 elastic layer to rigid layer. After 30 to 60 seconds, the elastic polymer composition and the rigid polymer composition are connected to each other and form a double-layer sealant, which continues to cure / strengthen over the next 10 minutes.

[0095] Example 4

[0096] Burst Pressure Testing of Sealant Compositions

[0097] Various sealant compositions were tested in a benchtop dural burst pressure assessment to evaluate various ratios of elastic polymer compositions to rigid polymer compositions. A linear incision of 15 mm in length was made in the harvested porcine dura and reapproximated to simulate a clinical dural tear condition. Next, 1.5 mL to 2.0 mL or 1.5 mm to 2 mm thickness of the elastic polymer composition and the rigid polymer composition were tested as controls. The thickness of each layer was modulated by varying the volume of each polymer composition applied to a constant tissue area. Pressure was generated beneath the tissue surface using a syringe pump at an infusion rate of 2 ml / min to 10 ml / min and tested until failure. The peak failure pressure and failure mode were recorded for each sample. The failure mode was defined as either cohesive failure within the sealant, or adhesive failure at the sealant and tissue interface. The results of the burst pressure testing are shown in Tables 1 and Figure 2A In the figure, the burst pressure (mmHg) test results of the dual-layer sealant of the present invention and a first control composition having only an elastic polymer composition and a second control composition having only a rigid polymer composition at various elastic layer to rigid layer ratios are shown. Compared to the control, the preferred range of the average diameter ratio of the provided dual-layer sealant polymer composition is from about 1:1 elastic layer to rigid layer to about 3:1 elastic layer to rigid layer.

[0098] Table 1

[0099]

[0100] The burst pressure test results of the double layer sealant at various percentage thicknesses of the elastic layer relative to the total double layer sealant thickness are shown in Figure 2B In the figure.

[0101] It was observed that a thickness of the elastomeric polymer composition of about 50% resulted in an increased burst pressure relative to the control or the dual layer sealant having less than or greater than 50% elastomeric polymer composition.

[0102] Example 5

[0103] Swelling test of sealant compositions

[0104] Extent of swelling of sealant compositions having various ratios of elastomeric polymer composition to rigid polymer composition. The sealant compositions were applied to cylindrical molds and allowed to fully cure. The sealant compositions were then soaked in PBS at 37°C for 6 days. The percent swelling of the sealant compositions was evaluated based on weight measurements from day 1 to day 6. Only the elastomeric polymer composition swelled to 180%. Only the rigid polymer composition swelled to 20%. Surprisingly, with only 33% of the bi-layer thickness consisting of the rigid polymer composition, the extent of swelling was reduced to about 100% (about 57% of the swelling observed in the elastomeric formulation alone). The results of the swelling tests are shown in Tables 2 and 3 below. Figure 3 In the figure.

[0105] Table 2

[0106]

[0107] Example 6

[0108] Evaluation of tensile properties of elastomeric and rigid sealant formulations

[0109] To prepare the elastomeric polymer composition of the double-layer sealant, first prepare a solution of 124 mg / mL 4-arm-PEG-amine (molecular weight 20,000) in 200 mM N-cyclohexyl-2-aminoethanesulfonic acid (CHES) buffer at 9.35 pH. Next, prepare a solution of 124 mg / mL 4-arm-PEG-succinimidyl glutarate (molecular weight 20,000) in purified deionized (DI) water. The final concentration of the mixed elastomeric polymer composition was 62 mg / mL 4-arm-PEG-NHS-20K, 100 mM CHES, and 62 mg / mL 4-arm-PEG SG-20K.

[0110] A Sulzer mixing dispensing tip was attached to the device, which was primed and then immediately extruded into 5 tensile dies. The samples were loaded onto the Instron test machine and tested after a 10 minute cure time. Testing was done with a 10N load cell, molded to ensure a 14.8mm gauge length and 18.29mm 2 The cross-sectional area was 1.37 mm / min and the test was performed at a rate of 40.0 mm / min. The results of this study are shown in Table 3 below.

[0111] Table 3

[0112]

[0113] It should be understood that certain features of the invention described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the invention described in the context of a single embodiment for simplicity may also be provided separately or in any suitable subcombination or as appropriate in any other described embodiment of the invention. Certain features described in the context of various embodiments should not be considered essential features of those embodiments unless the embodiment does not function without those elements.

[0114] Although various types have been shown and described in this disclosure, additional improvements to the methods and systems described herein may be achieved by those of ordinary skill in the art by appropriate modifications without departing from the scope of the invention. Several such possible modifications have been mentioned, and other modifications will be apparent to those of skill in the art. For example, the examples, types, geometries, materials, dimensions, ratios, steps, etc. discussed above are illustrative and not essential. Therefore, the scope of the present invention should be considered in light of the following claims and should be understood not to be limited to the details of the structure and operation shown and described in the specification and drawings.

Claims

1. A biodegradable double-layer sealant for tissue closure, the double-layer sealant comprising a first layer comprising an elastic polymer composition and a second layer comprising a rigid polymer composition, wherein the layer thickness ratio of the elastic polymer composition to the rigid polymer composition is about 1:1 to about 3:1, respectively. 2 . The double-layer sealant according to claim 1 , wherein the elastic polymer composition and the rigid polymer composition are linked by a covalent bond.

3. The double-layer sealant according to claim 1, wherein the elastic polymer composition and the rigid polymer composition are hydrogels.

4. The double layer sealant of claim 3, wherein the hydrogel comprises mutually reactive polyethylene glycol. The double-layer sealant according to claim 4 , wherein the polyethylene glycol is a multi-arm polyethylene glycol.

6. The double-layer sealant according to claim 1, wherein the rigid polymer composition further comprises a protein or a peptide and a cross-linking agent. The double-layer sealant according to claim 6 , wherein the protein is albumin.

8. The double-layer sealant according to claim 7, wherein the albumin is selected from the group consisting of bovine serum albumin, human serum albumin, recombinant human albumin, albumin variants and synthetic albumin.

9. The double-layer sealant according to claim 6, wherein the protein is selected from the group consisting of fibronectin, ovalbumin, lactalbumin, extracellular matrix protein, polylysine, and a combination of two or more thereof.

10. The double layer sealant of claim 6, wherein the double layer sealant has a burst pressure of at least about 80 mmHg.

11. The dual-layer sealant of claim 6, wherein the elastic polymer composition has an elastic modulus of about 19 kPa to about 24 kPa.

12. The dual layer sealant of claim 6, wherein the elastomeric polymer composition has an elongation at break of at least about 245%.

13. The double-layer sealant of claim 6, wherein the rigid polymer composition has an elastic modulus less than three times that of the elastic polymer composition and an elongation at break of about 100%.

14. The double-layer sealant of claim 6, wherein the sealant has a swelling percentage in an aqueous medium after 6 days at 37°C that is at least about 1.4 times lower than the swelling percentage of an elastic polymer composition having the same thickness in an aqueous medium after 6 days at 37°C.

15. The dual-layer sealant of claim 6, wherein the sealant has a swelling percentage of about 70% to about 110% as measured in an aqueous medium after 6 days at 37°C.

16. A method for tissue closure, the method comprising: (a) applying a first layer on a tissue, wherein the first layer comprises a biodegradable elastic polymer composition comprising multi-arm polyethylene glycol; (b) at least partially curing the first layer; and (c) applying a second layer on the surface of the elastic polymer composition, wherein the second layer comprises a biodegradable rigid polymer composition comprising multi-arm polyethylene glycol and a protein or peptide.

17. The method of claim 16, wherein the multi-arm polyethylene glycol is selected from the group consisting of 4-arm-PEG-amine, 4-arm-PEG-N-hydroxysuccinimide, 6-arm-PEG-N-hydroxysuccinimide, 4-arm-PEG-succinimidyl glutarate, 4-arm-PEG-succinimidyl carbonate, 4-arm-PEG-acrylate, 4-arm-PEG-succinimidyl valerate, 4-arm-PEG-succinimidyl succinate, 4-arm-PEG-succinimidyl butyrate, 4-arm-PEG-succinimidyl succinamide, 4-arm-PEG-succinimidyl propionate, 4-arm-PEG- -PEG-sulfosuccinimidyl glutarate (SG), 4-arm-PEG-sulfosuccinimidyl valerate, 4-arm-PEG-sulfosuccinimidyl carbonate, 4-arm-PEG-succinimidyl carboxymethyl ester, 4-arm-PEG-sulfosuccinimidyl succinate, 4-arm-PEG-sulfosuccinimidyl butyrate, 4-arm-PEG-sulfosuccinimidyl succinamide, 4-arm-PEG-sulfosuccinimidyl propionate, and 4-arm-PEG-isocyanate, 4-arm-PEG-imidate, and 4-arm-PEG-maleimide, and combinations of two or more thereof.

18. The method according to claim 16, wherein the protein is selected from the group consisting of albumin, fibronectin, ovalbumin, lactalbumin, extracellular matrix protein, polylysine, and a combination of two or more thereof.

19. The method of claim 16, wherein the layer thickness ratio of the elastic polymer composition to the rigid polymer composition is from about 1:1 to about 3:1; the elastic polymer composition has an elastic modulus of from about 19 kPa to about 24 kPa; and the rigid polymer composition has an elastic modulus of about less than three times that of the elastic polymer composition.

20. A kit for preparing a biodegradable double-layer sealant for closing tissue, the kit comprising a first storage container containing a first solution for preparing a biodegradable elastic polymer composition component and a second storage container containing a second solution, the first solution comprising a solution of multi-arm PEG in cyclohexyl-2-aminoethanesulfonic acid (CHES) buffer, and the second solution comprising a solution of multi-arm PEG in purified deionized water; a third storage container containing a third solution for preparing a biodegradable rigid polymer composition component and a fourth storage container containing a fourth solution, the third solution comprising a solution of a protein or peptide in sodium carbonate buffer, and the fourth solution comprising a solution of multi-arm PEG in purified deionized water; and wherein after applying the rigid polymer composition to the surface of the elastic polymer composition and curing the elastic polymer composition and the rigid polymer composition, the rigid polymer composition has an elastic modulus that is approximately less than three times that of the elastic polymer composition.

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