High-Elastic Medical Sealant for Soft Soft Tissues

Abstract

In this specification, a reactive liquid hydrogel sealant mixture containing an electrophilic compound capable of crosslinking, a nucleophilic compound, and an amphiphilic poly(alkyl) ethylene glycol block polymer in an amount of 20% (w / v) or less of the sealant composition is utilized to provide a composition, a system, and a surgical method for treating extensible soft tissue. The composition can optionally contain a thickening agent in an amount of 0.1% to 1.0% (w / v) of the sealant composition.

Description

Technical Field

[0001] The present disclosure describes a liquid composition for forming a crosslinked bioabsorbable elastic sealant suitable for use in the repair of expandable soft tissue.

Background Art

[0002] Crosslinkable mixtures of synthetic polymers and / or biologics are widely used as surgical sealants. These products typically begin as separate liquid components that react with each other upon application to form a strong crosslinked gel. In the design of surgical sealants, often the utility of the delivery device and the mechanical properties of the sealant mechanics are considered. With regard to utility, the viscosity of the sealant is essential to enable application tailored to the purpose of the sealant. The utility of the sealant is a direct result of the mechanics of the resulting gel and includes tensile properties, adhesion properties, and burst pressure. For example, when used as a pleural sealant, elasticity is important to maintain a durable and flexible seal during the expansion and contraction cycles of the lung. Currently available synthetic sealants have several drawbacks. For example, Progel™, an FDA-approved liquid sealant indicated for sealing pleural air leaks, has a low viscosity, is difficult to hold the solution at the desired application site, has insufficient stretchability, and peels from multiple surfaces during periodic lung expansion.

[0003] One solution to low viscosity is to incorporate rheology modifiers such as polysaccharides and natural rubbers to increase the viscosity of the liquid sealant, thereby reducing the outflow of the liquid phase. Typically, the viscosifying agent is selected in such a way that it does not react with the active components of the sealant. As a result, these agents do not provide further benefits to the elasticity or cohesiveness of the resulting gel and in some cases cause a decrease in elasticity, perhaps due to an adverse effect on mixing.

Summary of the Invention

Problems to be Solved by the Invention

[0004] Therefore, there is a need to provide a sealant for soft tissue that meets the clinical needs for elasticity and strength, has improved handling characteristics including viscosity, and can withstand cyclic expansion and contraction.

Means for Solving the Problems

[0005] The present disclosure is directed to compositions suitable for use as soft tissue sealants, particularly as pleural sealants. In order to function as a clinically effective tissue sealant, the sealant composition must have a sufficiently high viscosity prior to curing to inhibit flow from the anatomical site of application, maintain proper sealing, and exhibit a sufficiently high tensile strength and elongation after curing to prevent delamination of the sealant from the anatomical site.

[0006] Accordingly, the present disclosure describes a liquid composition for forming a cross-linked sealant suitable for use in the repair of expandable soft tissue. The liquid composition according to the present disclosure is a reactive hydrogel mixture of an electrophilic compound and a nucleophilic compound that are cross-linkable with each other via the reaction of the available electrophilic and nucleophilic moieties of each compound, an amphiphilic poly(alkyl) ethylene glycol block polymer, and a buffer solution having a pH in the range of about 8.5 to about 10.5. The electrophilic compound can include a multi-arm polyethylene glycol (PEG)-based polymer, and the nucleophilic compound can include a multi-arm polymer containing at least one reactive amine group or thiol group. Preferably, the liquid composition includes a buffer solution having a pH in the range of about 8.5 to about 9.0.

[0007] This disclosure describes improvements to biocompatible sealants demonstrating that the addition of an amphiphilic poly(alkyl) ethylene glycol block polymer in a suitable amount (<20% w / v) results in the unexpected benefits of increased viscosity of the liquid co-mixture and improved elasticity of the resulting hydrogel. This disclosure describes further improvements to the above sealants by the addition of a thickening agent such that the unexpected synergistic effect of the amphiphilic poly(alkyl) ethylene glycol block polymer and the thickening agent results in improved viscosity, elasticity, adhesiveness, and cohesiveness as compared to conventionally known biocompatible sealants. In addition to the improved sealant tensile properties, the addition of the amphiphilic poly(alkyl) ethylene glycol block polymer can provide benefits in terms of drug delivery potential. Amphiphilic poly(alkyl) ethylene glycol block polymers have the ability to encapsulate and deliver hydrophobic drugs, and those abilities can be utilized in the liquid compositions described herein to provide therapeutic benefits at the target anatomical site of application.

[0008] In certain embodiments, the amphiphilic poly(alkyl) ethylene glycol block polymer is present in the liquid composition in an amount in the range of about 20% (w / v) or less of the liquid composition, such as, for example, about 5% to about 15% (w / v), or about 7.5% to about 12.5% (w / v). In further embodiments, the amphiphilic poly(alkyl) ethylene glycol block polymer comprises basic units such as polyethylene glycol, polypropylene glycol, and copolymers thereof, such as triblock copolymers comprising a central block of polypropylene glycol and two terminal blocks of polyethylene glycol (PEG).

[0009] In additional embodiments, the liquid composition further comprises a thickening agent, or a mixture of at least two different thickening agents. In certain embodiments, the thickening agent comprises at least carboxymethyl cellulose (CMC) or carrageenan. In certain further embodiments, the thickening agent is present in the liquid composition in an amount in the range of about 0.1% to about 10% (w / v).

[0010] In certain embodiments, the electrophilic compound comprises at least one of 4-arm PEG-N-hydroxysuccinimide (PEG-NHS), or more specifically 4-arm PEG-succinimidyl glutarate ester (PEG-SG). In certain further embodiments, the nucleophilic component comprises at least one of 4-arm PEG-amine or albumin.

[0011] The present disclosure further describes a system for forming a crosslinked sealant for use in soft tissue repair and treatment. According to certain embodiments, this system can comprise a first container containing a first liquid and a second container containing a second liquid, the first liquid having a buffered solution with a pH in the range of about 8.5 to about 9.0, a crosslinkable electrophilic compound, and an amphiphilic poly(alkyl) ethylene glycol block polymer, the second liquid having a buffered solution with a pH in the range of about 8.5 to about 9.0, and a crosslinkable nucleophilic compound, the electrophilic compound and the nucleophilic compound being crosslinkable to each other via reaction of the available electrophilic and nucleophilic moieties of each compound. In the disclosed system, the crosslinkable electrophilic compound and the crosslinkable nucleophilic compound are configured to form a crosslinked soft tissue sealant upon mixing of the first liquid and the second liquid. According to a further embodiment, the first container can further comprise a thickening agent as described above.

[0012] The present disclosure is further a surgical method of treating or repairing soft tissue, such as pleural tissue, mixing a first liquid contained in a first container and a second liquid contained in a second container to form a liquid soft tissue sealant, the first liquid comprising a buffered solution having a pH in the range of about 8.5 to about 9.0, a crosslinkable electrophilic compound, and an amphiphilic poly(alkyl) ethylene glycol block polymer, the second liquid comprising a buffered solution having a pH in the range of about 8.5 to about 9.0, and a crosslinkable nucleophilic compound, Forming a liquid crosslinked tissue sealant from a mixture of a first and a second fluid; Applying the liquid crosslinked tissue sealant to pleural tissue to cover a target surface. BRIEF DESCRIPTION OF THE DRAWINGS

[0013]

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DETAILED DESCRIPTION OF THE INVENTION

[0014] As used herein, the words "a" or "an" are used to include one or more than one, and the word "or" is used to refer to non - exclusive "or" unless otherwise specified. Further, it should be understood that the grammar or terminology used herein and not otherwise defined is for illustrative purposes only and not for limiting purposes. When a range of values is expressed, in other embodiments, certain specific values from and / or up to other specific values are included. Similarly, when a value is expressed in approximate form by the preceding "about", it will be understood that other embodiments are formed by that specific value. All ranges include boundary values and combinations are possible. Further, references to values described in a range include any value within that range. It will also be recognized that certain features of the invention described herein as separate embodiments for clarity may also be presented in combination in a single embodiment. Conversely, various features of the invention described as a single embodiment for brevity may also be presented separately or in any sub - combination.

[0015] As used herein, the phrase "consisting essentially of" is intended to define a claim as including the recited components, compounds, substances, materials, or steps, and further including any component, compound, substance, material, or step that does not materially affect the basic characteristics of the claimed invention.

[0016] The present disclosure describes a liquid composition for forming a cross - linkable sealant suitable for use in the repair of extensible soft tissue. Preferably, the soft tissue is pleural tissue. The liquid composition according to the present disclosure is a reactive hydrogel mixture of an electrophilic compound and a nucleophilic compound that are cross - linkable with each other via the reaction of available electrophilic and nucleophilic moieties of each compound, an amphiphilic poly(alkyl) ethylene glycol block polymer, and a buffer solution having a pH in the range of about 8.5 to about 9.0.

[0017] Electrophilic and nucleophilic reactive compounds that form the cross-linked structure of the hydrogel sealant are known in the art and can include both synthetic polymers (e.g., multi-arm polyethylene glycol (PEG) - based polymers) and natural substances, as well as combinations thereof. Multi-arm PEGs suitable for the elastic layer can include 2, 3, 4, 6, or 8 multi-arm PEGs. In a preferred embodiment, the multi-arm PEG has a molecular weight of about 2 kDa to about 40 kDa.

[0018] According to certain embodiments, the synthetic polymer can include polymers having activated esters from classes of compounds such as PEG-N-hydroxysuccinimide (PEG-NHS), PEG-aldehyde, PEG-acrylate, carboxyl-PEG, and 4-arm vinyl-PEG. According to further embodiments, a non-exhaustive list of suitable electrophilic compounds includes 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 butanoate, 4-arm-PEG-succinimidyl succinamide, 4-arm-PEG-succinimidyl propionate, 4-arm-PEG-sulfosuccinimidyl glutarate (SG), 4-arm-PEG-sulfosuccinimidyl valerate, 4-arm-PEG-sulfosuccinimidyl carbonate, 4-arm-PEG-sulfosuccinimidyl succinate, 4-arm-PEG-sulfosuccinimidyl butanoate, 4-arm-PEG-sulfosuccinimidyl succinamide, 4-arm-PEG-sulfosuccinimidyl propionate, and 4-arm-PEG-isocyanate, 4-arm-PEG-imidoester, 4-arm-PEG-maleimide, 4-arm-PEG-acetic acid, 4-arm-PEG-propanoic acid, 4-arm-PEG-butyric acid, 4-arm-PEG-hexanoic acid, and 4-arm-PEG-vinyl sulfone. Other examples include 2-arm, 3-arm, 6-arm, and 8-arm-PEG of the exemplary 4-arm compounds listed above. As described above, the electrophilic compounds can include blends of natural and synthetic components.

[0019] In certain embodiments, the nucleophilic compound includes natural compounds such as albumin, gelatin, or collagen. In certain further embodiments, the nucleophilic compound can include a synthetic polymer, preferably a multi-arm polymer. In a further embodiment, the nucleophilic compound contains at least one reactive amine group such as, for example, 4-arm PEG-amine or PEG-hydrazide, or 4-arm PEG-thiol.

[0020] Suitable amphiphilic poly(alkyl) ethylene glycol block polymers according to the present disclosure include, for example, compounds from the class of polyether polyols such as polyethylene glycol (PEG) and polypropylene glycol (PPG), as well as copolymers and mixtures thereof. In a preferred embodiment, the block polymer is a diblock polymer or triblock polymer containing both PEG units and PPG units. For example, one suitable class of compounds is generally known as poloxamers and includes triblock copolymers composed of a central hydrophobic block of PPG flanked by two hydrophilic chains of PEG, triblock copolymers consisting of a central hydrophobic block of polypropylene glycol flanked by two hydrophilic blocks of polyethylene glycol (PEG). Poloxamers are also generally known under the trade name Pluronic. A particularly preferred embodiment is Poloxamer 407 (also known as Pluronic F127).

[0021] According to the present disclosure, the amphiphilic poly(alkyl) ethylene glycol block polymer is present in an amount of 20% (w / v) or less of the sealant composition, preferably in the range of about 5% to about 15% (w / v), and particularly preferably in the range of about 7.5% to about 12.5% (w / v) of the sealant composition.

[0022] In certain embodiments, the liquid composition according to the present disclosure consists essentially of a reactive hydrogel mixture of a crosslinkable electrophilic compound and a nucleophilic compound, an amphiphilic poly(alkyl) ethylene glycol block polymer, and a buffer solution having a pH in the range of about 8.5 to about 9.0. In a preferred embodiment, the liquid composition according to the present disclosure consists essentially of PEG-NHS, such as 4-arm PEG-SG, 4-arm PEG-amine or albumin, a triblock copolymer comprising a central block of PPG and two terminal blocks of PEG, and a buffer solution having a pH in the range of about 8.5 to about 9.0.

[0023] The present disclosure further describes formulations of the liquid compositions described above that include one or more thickening agents in combination with the amphiphilic poly(alkyl) ethylene glycol block polymers described above. Thickening agents are well known in the field of biocompatible sealants. Exemplary thickening agents can include, for example, carrageenan (iota, kappa, and lambda), starch (including corn starch), cellulose (including carboxymethyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose), alginates, agar (including agarose), glycerol, pectin (including apple pectin, citrus pectin), gums (including guar, gellan, xanthan, locust bean), and gelatin. According to certain embodiments, the thickening agent includes a mixture of at least two different thickening agent compounds. In a further embodiment, the thickening agent includes at least one of carboxymethyl cellulose (CMC) or carrageenan, and in still a further embodiment, includes a mixture of CMC and carrageenan.

[0024] According to embodiments of the present disclosure, the thickening agent is present in the composition in an amount in the range of about 0.1% to about 10% (w / v). In a preferred embodiment, the thickening agent is present in the composition in an amount in the range of about 0.1% to about 5.0% (w / v). In still a further embodiment, the thickening agent is present in the composition in an amount in the range of about 0.1% to about 1.0% (w / v). In certain embodiments that include a mixture of at least two thickening agent compounds, at least one of the thickening agent compounds is present in an amount in the range of about 0.1% to about 1.0%.

[0025] As described above, in certain embodiments, at least two different thickeners can be combined for a synergistic thickening effect, where their interaction creates a new texture and accelerates the thickening time. For example, ι-carrageenan, when combined with starch, can increase the viscosity of the solution up to 10 times that of a solution of starch alone. These synergistic effects can potentially be very useful in the liquid sealants according to the present disclosure for two-fold benefits: 1) lower concentrations of the additives acting synergistically can be used, which can address potential toxicity issues due to higher concentrations of a single additive, and 2) the lower concentrations can also result in cost reduction.

[0026] Carrageenan is a family of high molecular weight linear polysaccharides composed of sodium, potassium, and magnesium and calcium sulfates of galactose and 3,6-anhydrogalactose copolymers. The viscosity of a carrageenan solution depends on the molecular weight, concentration, and temperature, as well as the presence of other solutes. Carrageenan viscosity typically increases exponentially with concentration. There are three main types of carrageenan, each with a different degree of sulfation, namely λ-carrageenan having three sulfate groups per disaccharide, γ-carrageenan having two sulfate groups, and κ-carrageenan having one sulfate group. Higher ester sulfates require lower temperatures to solubilize the additive.

[0027] All three forms of carrageenan are water-soluble, but dissolution is affected by the type of carrageenan, counterion, solute, temperature, and pH. Due to the level of sulfation, λ-carrageenan is the most soluble of the three. ι-carrageenan is intermediate, but exhibits hydrophilic behavior because its two sulfates can counteract the lower hydrophilic properties of the 3,6-anhydrogalactose residues. Carrageenan is known to maintain good stability at neutral and alkaline pHs and is thus a good potential additive for soft tissue liquid sealants typically composed of moderately alkaline buffers.

[0028] Starch, which is a linear chain of glucose units linked by glycosidic bonds, has limited solubility, which can pose problems for its use in standard sealant manufacturing processes. Isolated starch is substantially insoluble in cold water, alcohol, and most organic solvents due to hydrogen bonding and molecular crystallinity. Furthermore, aggregation occurs readily because the polymer swells substantially upon contact with water. Temperature, pH, heating rate, and the presence of other salts all affect starch. Additionally, shear force and pressure-induced mixing can change the solubility and final viscosity of starch. To aid in solubility improvement, a small amount of starch can be added to water to form a gel or paste, which is then diluted and more granules are slowly added while heating to reach the desired concentration.

[0029] Cellulose-derived carboxymethyl cellulose (CMC) is composed of carboxymethyl groups attached to the hydroxyl groups of glucopyranose monomers along the cellulose backbone. The carboxymethyl groups function as acids, making CMC an anionic polyelectrolyte. CMC is essentially hydrophilic, swelling in water and forming aggregates and lumps. The shear forces applied during any mixing process containing CMC can affect the final viscosity of the solution. The dissolution rate and viscosity can also be affected by concentration and temperature, while pH and electrolytes can have a lesser effect. As the temperature increases, the viscosity decreases, but this is reversible, and the original viscosity can be restored when the temperature returns to the starting value. CMC is stable over a wide range of pH values, being affected only by alkaline hydrolysis at levels above 11, and at levels below 4, cations are replaced by hydrogen, rendering the molecule insoluble in water. The effect of electrolytes on viscosity depends on the ability of the cations to form soluble salts with the molecule, which depends on the concentration of the salt and CMC. When exposed to electrolytes, CMC molecules will coil up, changing their conformation and thus reducing the viscosity.

[0030] Alginates are water-soluble hydrophilic colloid biopolymers. They are anionic polymers composed of a linear backbone of (1-4)-linked β-D-mannuronate (mannuronate, M) and its C-5 epimer α-L-guluronate (guluronate, G) residue homopolymer blocks. The dissolution of alginates typically requires vigorous stirring along with slow addition to the solvent to prevent lump formation and aggregation. Premixing with liquids in which the alginate is insoluble, such as alcohol or PEG, enhances dispersion and promotes dissolution. Concentration and temperature are expected to affect both dissolution and the final viscosity of the solution. Since alginates have pseudoplastic properties, shear rate also plays a role, with viscosity decreasing as the shear rate increases. Finally, alginates are much more susceptible to microbial attack than other carbohydrate-based additives and, when compromised, cause a decrease in viscosity.

[0031] In certain embodiments, the liquid composition according to the present disclosure consists essentially of a reactive hydrogel mixture of an electrophilic compound and a nucleophilic compound that are crosslinkable with each other via the reaction of the available electrophilic and nucleophilic moieties of each compound, an amphiphilic poly(alkyl) ethylene glycol block polymer, a thickening agent, and a buffer solution having a pH in the range of about 8.5 to about 9.0. In preferred embodiments, the liquid composition according to the present disclosure consists essentially of a PEG-NHS such as 4-arm PEG-SG, a 4-arm PEG-amine or albumin, a triblock copolymer comprising a central block of PPG and two terminal blocks of PEG, a mixture of CMC and ι-carrageenan, and a buffer solution having a pH in the range of about 8.5 to about 9.0.

[0032] The present disclosure further describes a system for forming a crosslinked sealant for use in the repair and treatment of soft tissue. According to certain embodiments, the system can include a first container containing a first liquid and a second container containing a second liquid, the first liquid having a buffer solution having a pH in the range of about 8.5 to about 9.0, a crosslinkable electrophilic compound, and an amphiphilic poly(alkyl) ethylene glycol block polymer, and the second liquid having a buffer solution having a pH in the range of about 8.5 to about 9.0 and a crosslinkable nucleophilic compound. In the disclosed system, the crosslinkable electrophilic compound and the crosslinkable nucleophilic compound are configured to form a crosslinked soft tissue sealant upon mixing of the first liquid and the second liquid.

[0033] The present disclosure further provides a surgical method for treating or repairing soft tissue, such as pleural tissue, mixing a first liquid contained in a first container and a second liquid contained in a second container to form a liquid soft tissue sealant, the first liquid including a buffer solution having a pH in the range of about 8.5 to about 9.0, a crosslinkable electrophilic compound, and an amphiphilic poly(alkyl) ethylene glycol block polymer, and the second liquid including a buffer solution having a pH in the range of about 8.5 to about 9.0 and a crosslinkable nucleophilic compound, Forming a liquid cross-linked tissue sealant from a mixture of a first and a second fluid; Applying the liquid cross-linked tissue sealant to cover the target pleural tissue surface.

Example

[0034] Example 1: Effects on Ultimate Elongation and Ultimate Stress in a Modified Base Sealant Formulation (Biosynthetic)

[0035] Materials: Base formulation - 75 mg / mL 4-arm PEG-SG-20k (electrophile), 10% albumin (nucleophile), 50 mM carbonate buffer, pH = 9.0 Additives - 0.1% i-carrageenan (thickener), 1% carboxymethyl cellulose (thickener), 5% poloxamer 407 (amphiphilic poly(alkyl) ethylene glycol block polymer) (approximate MW = 12.6 kD).

[0036] In the first experiment, three samples of the base formulation were measured for ultimate elongation against two separate formulations containing a thickening agent compound (four samples containing the base formulation and 0.1% i-carrageenan, and five samples containing the base formulation and 1.0% CMC).

[0037] In the second experiment, ten samples of the base formulation were measured for ultimate elongation against three samples containing the base formulation and 5% poloxamer 407.

[0038] In the third experiment, ten samples of the base formulation were measured for ultimate elongation against three samples containing the base formulation and 5% poloxamer 407, and four samples containing the base formulation, 5% poloxamer, and 1% CMC / 0.2% i-carrageenan.

[0039] In the fourth experiment, the ultimate stress was measured for 10 samples of the base formulation, 3 samples containing the base formulation and 5% poloxamer 407, and 4 samples containing the base formulation, 5% poloxamer, and 1% CMC / 0.2% i-carrageenan.

[0040] In this study, the curing time of the tested sealants was 10 minutes.

[0041] The ultimate stress, ultimate strain, and elastic modulus were calculated in MATLAB R2018. Statistical analysis was performed in Minitab v18. Tensile tests measured the elongation at complete failure of the sealant when tested in the vertical tensile direction at 5 mm / min. Custom fixtures made from Teflon were designed to create a "dog bone" shape and extrude the sealant, allowing them to be attached to an Instron Materials Tester. As the crosshead moves vertically, the fixtures are pulled apart and the strength and elongation of each sample are measured. Failure was defined as the point when the sealant completely broke within the fixture.

[0042] The results are shown in Figures 1A - 1D. Referring to Figure 1A, there was no statistically measurable difference in ultimate elongation between the three formulations from the first run (two-sample t-test). Referring to Figure 1B, in the second run, the ultimate elongation between the two groups was statistically different (p = 0.046, two-sample t-test), showing an increase in ultimate elongation for the samples containing poloxamer 407. Referring to Figure 1C, similar to the results shown in Figure 1B, there was a statistically significant difference in ultimate elongation between the base formulation and the two formulations containing poloxamer 407. However, there was no statistical change in ultimate elongation between the two formulations containing poloxamer 407 with the added thickener (one-way ANOVA analysis). Finally, referring to Figure 1D, there was a statistically significant increase in the ultimate stress of the test samples containing the thickener compared to the two formulations without the thickener (p = 0.00, one-way ANOVA).

[0043] Example 2: Effect of various amphiphilic poly(alkyl) ethylene glycol block polymer concentrations on the tensile properties of a sealant formulation (biosynthesis) Pluronic F127 (an amphiphilic poly(alkyl) ethylene glycol block polymer) [the BASF trade name for the above-mentioned poloxamer 407] was dissolved in 100 mM carbonate buffer (pH = 8.0) at 0, 0.1, 0.3, 2, 5, 10, 15, 20, 25, and 30% (w / v). 5 mL of the Pluronic solution was added to 750 mg of PEG-SG4-20k and dissolved for 5 minutes. The solution was filled into a 20 mL syringe and attached via a double syringe connector to a 20 mL syringe containing 5 mL of 20% albumin (dissolved in water). The solution was passed through 10 times back and forth to generate a sealant. The sealant was immediately injected into a tensile mold for testing.

[0044] The tensile test measures the elongation at complete failure of the sealant when tested in the vertical tensile direction at 5 mm / min. Custom fixtures made from Teflon were designed to create a "dog bone" shape and extrude the sealant, thereby enabling them to be attached to an Instron Materials Tester.

[0045] As the crosshead moves vertically, the fixture is pulled apart and the strength and elongation of each sample are measured. Failure was defined as the point at which the sealant completely broke within the fixture.

[0046] In this study, the curing time of the sealants tested was 10 minutes. The ultimate stress, ultimate strain, and modulus of elasticity were calculated in MATLAB R2018. One-way ANOVA was performed to provide a statistical comparison between groups.

[0047] Referring to Fig. 2A, there was a significant increase in the ultimate elongation as the concentration of Pluronic F127 increased (p < 0.01, one-way ANOVA, Appendix). Referring to Fig. 2B, the ultimate stress (p < 0.01, one-way ANOVA, Appendix) value increased maximally at approximately 10% concentration and then decreased thereafter with further Pluronic F127 concentration. The ultimate elongation increased on average over the entire range of concentrations tested, while the ultimate stress increased statistically at concentrations of 5% - 15% and peaked at 7.5% - 12.5%.

[0048] Example 3: Effect of Amphiphilic Poly(alkyl) Ethylene Glycol Block Polymer Concentration on Tensile Properties of Sealant Formulations (Fully Synthetic) Materials:

[0049] [Table 1]

[0050] In this study, a three-factor general factorial design was utilized. PEG-amine was tested at three levels, and PEG-SG and Pluronic were tested at two levels. Pluronic F127 was dissolved in 100 mM carbonate buffer (pH = 8.0). 5 mL of the Pluronic solution was added to 750 mg of PEG-SG4-20k and dissolved for 5 minutes. The solution was filled into a 20 mL syringe and attached via a double syringe connector to a 20 mL syringe containing 5 mL of the PEG-amine solution. The solution was passed back and forth approximately 10 times to generate the sealant. The sealant was immediately injected into a tensile mold for testing.

[0051] The tensile test measures the elongation at complete failure of the sealant when tested in the perpendicular tensile direction at 5 mm / min. Custom fixtures made from Teflon instead of aluminum were created to form a "dog bone" shape and designed to extrude the sealant, thereby enabling their attachment to an Instron Materials Tester. As the crosshead moves vertically, the fixtures are pulled apart and the strength and elongation of each sample are measured. Failure was defined as the point at which the sealant completely failed within the fixture.

[0052] In this study, the curing time of the sealants tested was 10 minutes. The ultimate stress, ultimate strain, and modulus of elasticity were calculated in MATLAB R2018. Statistical analysis was performed in Minitab v18.

[0053] Referring to FIGS. 3A - 3C, the analysis of the main effects showed that as PEG - SG decreased and Pluronic increased, the ultimate elongation of the formulation increased. As PEG - SG increased and Pluronic increased, the ultimate stress increased. As PEG - SG increased and Pluronic decreased, the rigidity increased. On the other hand, PEG - amine did not linearly affect the tensile properties. As the concentration of PEG - amine increased from 28.5 to 57 mg / mL, the properties did not change significantly. However, at 57 - 114 mg / mL, the ultimate elongation increased and the ultimate stress and rigidity substantially decreased. The results showed that PEG - SG, Pluronic, and their interaction had a significant effect on the ultimate elongation. PEG - amine and PEG - SG had a significant effect on the ultimate stress. PEG - amine, PEG - SG, and Pluronic had a significant effect on the rigidity.

[0054] Example 4: Analysis of the thickener formulation This study investigated the combinations of individual viscosity - enhancing additives and their control formulations while maintaining or improving the functional material properties.

[0055] Materials - The components used in the formulations tested below are as follows.

[0056] PEG-SG (4-arm), MW: 20 kDa, [Jenkem] Bovine serum albumin, [Sigma A7030] Sodium carbonate, [Sigma 223484] ι-carrageenan, [TCI C1805] λ-carrageenan, [TCI C3313] Ultra-Sperse® corn starch, [Ingredion] Carboxymethyl cellulose (CMC) sodium salt (HV), [Sigma C5013] Sodium alginate salt derived from brown algae, [Sigma A2033] Pluronic® F-127, [Sigma P2443]

[0057] Example 4A: Preparation of Liquid Sealant Groups Ten groups of liquid sealant additives or additive combinations were used in this study. The control condition without additives was composed of PEG-SG4-20K. For each experimental group, at least three concentrations of the additive(s) were first qualitatively evaluated for ease of dissolution and generation / maintenance of enhanced viscosity in carbonate buffer (pH 9.0). Conditions requiring excessively high temperatures (e.g., >5% starch), conditions with undissolved solutes (e.g., >5% starch), or conditions generating bubbles (e.g., >20% Pluronic F-127) were excluded. Minor modifications to the experimental groups and / or additional controls were generated and used in different evaluations according to subset purposes. Table 2 below shows the sealant compositions prepared for the tests.

[0058]

Table 2

[0059] Example 4B: Evaluation of Dissolution Additives and additive combination groups were added to the carbonate buffer, and first, the ease or difficulty of dissolution was evaluated and compared within the groups. A semi - quantitative scoring system of 1 - 3 was generated to evaluate the number of steps. Score 1 indicates a 1 - step process, score 2 indicates 1 - 2 steps, and score 3 indicates >3 steps, which is shown in Table 3 below. As an example, the 5% starch group had a score of 3 because for dissolution, it was necessary to slowly add the powder through a funnel into the boiling carbonate buffer solution in the motion / vortex formed by a stirrer (a 3 - step process requiring particle wetting, rapid mixing, and high heat). All additives in this study were found to cause severe aggregation and lump formation when added directly to the carbonate buffer. Gentle addition for individual particle wetting, stirring / vortexing, heat, and / or time was required to some extent for all additives (some more than others). Starch, CMC, alginate, and any combination incorporating starch were the most labor - intensive and difficult to completely solubilize. Starch, in most cases, required boiling temperature to completely dissolve, making the choice of additives inadequate from a processing perspective.

[0060]

Table 3

[0061] Example 4C: Evaluation of Hydration (Figure 4) PEG - SG4 - 20K powder was added to the viscosity - enhancing carbonate buffer to prepare a 150 mg / mL solution. This solution was mixed by double - syringe exchange using a 5 mL BD syringe and a graduated - connector. To evaluate the hydration time, the number of pumps required for the PEG to visually dissolve was recorded as a rate measure. For measurement consistency, only one operator performed this test and passed each syringe at a rate of 1 pump / 2 seconds. A virtual metronome was used as a guide to maintain accuracy.

[0062] The hydration time of PEG-SG4-20K powder in the viscosity-enhanced carbonate buffer by dual syringe exchange varies depending on the type of additive, which can be seen in Figure 4. The 3% alginate and 2% CMC conditions took the longest (over 2 minutes). This time frame may pose a problem in a clinical setting. Unexpectedly, certain additive combinations such as 0.25% ι-carrageenan and 0.75% λ-carrageenan showed a high level of dynamic viscosity but dissolved PEG relatively quickly.

[0063] Example 4D: Evaluation of Polymerization To extrude the actual sealant, each viscosity-enhanced 150 mg / mL PEG-SG4-20K solution and 20% bovine serum albumin (BSA) formulation were filled into an Evicel delivery device attached to a prototype alternating viscous mixing tip. 1 mL of the sealant was extruded onto a 1-inch weighing boat containing 6 mm silicone beads on a 20-degree nating rocker. The time required for the beads to stop moving reflected the polymerization time for each condition. This procedure was repeated (n = 2) for each condition. The results for each test sample are shown in Figure 5.

[0064] Since gelation was completed in 75 seconds or less, the polymerization time was generally relatively reasonable for all viscous sealant groups. To provide a suitable clinical target time, preferably 30 seconds or less, some of these formulations may require additional modifications (e.g., concentration, pH change, and mixing) to shorten the polymerization time. For example, an additional 0.13% i-carrageenan formulation with a higher pH was tested in this experiment as a secondary control. The higher pH resulted in substantially faster polymerization with an average time of 12.5 seconds. Without being bound by any particular theory, increasing the pH may be a factor for shortening and controlling the polymerization time.

[0065] Example 4E: Sealant Flow Rate, Stop Distance, and Expression The flow rate and stopping distance of the sealant provide important information regarding the fluidity of the viscous sealant. In the case of liquid sealants, the main objective is to reduce the flow rate, but if the additive has a significant impact on the polymerization time (resulting in a longer stopping distance), the highly viscous sealant will be substandard (or ineffective).

[0066] After filling each sample and 20% bovine serum albumin (BSA) into the Evicel delivery device attached to the prototype alternating viscous mixing chip, 2 mL of the sealant was extruded in triplicate onto a 15-degree glass inclined plane (n = 3). A camera was placed perpendicular to the surface of the inclined plane to capture and calculate the flow rate and distance by photo and video, respectively. The flow rate was reported in inches per second and the stopping distance was reported in inches (6 inches = maximum distance on the plane).

[0067] Referring to Figure 6, compared to the control, the thickener formulations had substantially lower flow rates, but this did not result in a corresponding decrease in the stopping distance for these samples (each error bar was constructed using the 95% confidence interval of the mean. Sample size, n = 3 for each group). Some sealant groups with high concentrations of thickeners (e.g., 1% CMC) had relatively high viscosities but flowed gradually over longer distances. However, other formulations such as 2.5% starch performed inadequately in both evaluations. Unexpectedly, formulations containing two or more thickeners (each having a relatively low concentration) generally functioned better in that they produced very low flow rates without compromising polymerization, as reflected by the short stopping distances.

[0068] During the course of the above tests, the expression force, thickness, and stretch / strength of the individual formulations were semi-quantitatively evaluated on a scale of 1 to 3. The expression force was based on tactile feedback, but after carefully separating the sealant from the glass, the thickness was measured at the top of the slope. Stretch (elongation) and strength (resistance to the breaking point) were essentially tactile and were qualitatively evaluated by hand after carefully separating the sealant from the glass. For expression force and stretch / strength, a score of 1 was the lowest level and 3 was the highest. For thickness, a score of 1 indicated a measured value of <0.6 mm, 2 was 0.6 - 1 mm, and 3 was >1 mm. The results are shown in Table 3 below.

[0069]

Table 4

[0070] The expression force of the various thickener formulations, as well as the thickness and stretch / strength of the hydrogels, provided important characteristic insights and distinctions from the controls. Formulations containing CMC and alginates (alone and in combination) had the highest expression force values. In some cases, this resulted in thicker coatings. Although qualitative, some of these groups also resulted in high stretch / strength. Unexpectedly, the formulations containing F127 and thickeners had stretch / strength that exceeded all other test formulations.

[0071] Example 4F: Tensile Properties of Viscous Liquid Sealants The tensile test measures the tensile strength and elongation at complete failure of the sealant when tested in the perpendicular tensile direction at 5 mm / min. Custom fixtures were fabricated from Teflon and designed to create a "dog bone" shape for extruding the sealant, thereby enabling their attachment to an Instron Materials Tester. Each of the viscous sealant groups was extruded within these fixtures using an Evicel delivery device attached to a test prototype alternating viscous mixing tip. As the crosshead moves vertically, the fixtures are pulled apart and the strength and elongation of each sample are measured. Failure was defined as the point when the sealant completely failed within the fixture. At least three samples were tested for each group (n > 3).

[0072] The tensile test provides important distinctions and information regarding the elongation and stiffness biomaterial properties of viscous liquid sealants. Referring to Figure 7, box plots are shown along with the results of tensile test data regarding the elongation, maximum load, and stiffness of the sample formulations. Regarding elongation, the test revealed two groups that differed from the remaining formulations: the "ι-Carr, 10K" and "F127+CMC+ι-Carr" groups. The "ι-Carr, 10K" formulation functioned inadequately compared to the remaining samples, with a significantly lower percentage of elongation at failure. In contrast, the "F127+CMC+ι-Carr" formulation had a significantly higher elongation rate than the other formulations. To further illustrate this unexpected improvement, Figure 8 shows the comparative load-elongation curves for all the samples tested above, and three samples from the group with the F127 poloxamer showed unexpectedly significant superiority over the other formulations. The test was performed continuously on three samples for each group at a curing time of 10 minutes and then again after 10 minutes of curing time, which showed a continuation of further improvement after curing. The "F127+CMC+ι-Carr" formulation had a higher average elongation than the control, similar to the other formulations.

[0073] Example 4G: Tissue Adhesion Properties of Viscous Liquid Sealants The tissue adhesion test measures the maximum adhesion load of the sealant between two tissue surfaces in the vertical direction. The test was conducted according to ASTM F2258-05. Specific modifications to the ASTM test protocol included a circular platen (1 square inch area) and a 3 mm gap between the two platen surfaces. Porcine pleural samples (Farm to Pharm-Warren, NJ) were attached to the platens, and the test fixture was attached to an Instron Materials Tester. Each of the viscous sealant formulations was extruded into these fixtures using an Evicel delivery device attached to a prototype alternating viscous mixing tip for testing. A low-volume load cell was used to evaluate the force between the two tissue surfaces. When the test was started, the crosshead of the Instron moved vertically at a rate of 5 mm / min until failure. The failure mode was defined as cohesive failure within the foam or adhesive failure at the interface between the foam and the tissue.

[0074] Referring to Figure 9, the results from the tissue adhesion tests showed that "ι-Carr, 10K", "ι-Carr + λ-Carr", and "F127 + CMC + ι-Carr" functioned at least 25% better than the ELS control. Considering that previous findings confirmed that sealant formulations with PEG-SG4-10K were stiffer, the "ι-Carr, 10K" group was expected to withstand higher loads. However, the other formulations contained additives that not only improved viscosity but also provided benefits for tissue adhesion. As shown in Table 5 below, the failure mode was cohesive in almost all cases. For the group with F127, it may be important to note that "O-ring failure" of the fixture occurred where there was not even obvious visual deformation at the tissue-sealant interface. This may suggest that the formulation could withstand even higher loads than those recorded.

[0075]

Table 5

[0076] Example 4H: Rupture Characteristics of Viscous Liquid Sealants The rupture test method measured the maximum rupture pressure and failure mode of each formulation when applied to the excised porcine pleural samples. Pleural tissue was freshly harvested and provided by Farm to Pharm (Warren, NJ) prior to use. A single 1 mm diameter defect was created in the mounted tissue sample and purged with air prior to each application. Each of the viscous sealant groups was extruded in these fixture wells using an Evicel delivery device attached to a prototype alternating viscous mixing tip for testing. A syringe pump was used to generate pressure beneath the tissue surface at an infusion rate of 2 ml / min and tested until failure. The peak pressure at failure and the failure mode were recorded for each sample. The failure mode was defined as cohesive failure within the sealant or adhesive failure at the foam and tissue interface.

[0077] Referring to Figure 10, the box-and-whisker plot shows the maximum rupture test. The results showed relatively high rupture pressures for all formulations. Note that the "5% F127 + 0.1% ι-Carr + 0.5% CMC" solution had a lower pH compared to the other formulations. Based on the sample size and mean comparison obtained from the Tukey HSD method, all sample formulations containing thickeners were at least equal to the control. The "Alginate + λ-Carr" sample had a significantly higher mean rupture pressure of 410.68 mmHg, which was 105% higher than the control. This formulation also had a significantly higher rupture pressure when compared to the "ι-Carr, 10K" and "ι-Carr + starch" formulations. Referring to Table 6 below, the failure mode of tissue adhesion in this rupture test showed a mixed case of adhesive and cohesive failure, which was different from that seen in the above tissue adhesion test (Table 5). Interestingly, the control and formulations containing F127 failed only adhesively, while the samples containing high concentrations of CMC and alginate failed only cohesively.

[0078] The sealant formulations described herein have demonstrated not only an overall viscosity improvement that enables retention at the site of application, but also a benefit to the aggregation of the cross-linked network of the sealant. Tensile evaluations have demonstrated an improvement in elastic strength without sacrificing other performance characteristics of the sealant. Further, the linearity of the hydrogel in strain proportional to the magnitude of the applied stress suggests that the formulation can be readily adjusted to meet the compliance of various body tissues while improving overall handling characteristics. As shown and described above, the sealant formulations according to the present disclosure utilize various known biocompatible cross-linking reactants and show high potential for effective performance and applicability, thereby being advantageous to both patients and surgeons.

[0079] [Embodiments] (1) A liquid composition for forming a cross-linked sealant for expandable soft tissue, comprising a reactive hydrogel mixture comprising an electrophilic compound and a nucleophilic compound, wherein the electrophilic compound comprises a multi-arm polyethylene glycol (PEG)-based polymer, the nucleophilic compound comprises at least one reactive amine group, and the electrophilic compound and the nucleophilic compound are cross-linkable with each other via the reaction of the available electrophilic and nucleophilic moieties of each compound; an amphiphilic poly(alkyl) ethylene glycol block polymer in an amount of 20% (w / v) or less of the sealant composition; a buffer solution having a pH in the range of about 8.5 to about 10.5, wherein the composition has a final cross-linked hydrogel phase having an ultimate elongation in the range of about 15 mm to about 40 mm and an ultimate tensile stress in the range of about 2.4 kPa to 5.9 kPa. (2) The liquid composition according to embodiment 1, wherein the buffer solution has a pH in the range of about 8.5 to about 9.0. (3) The liquid composition according to embodiment 1 or 2, further comprising a viscosifier. (4) The liquid composition according to embodiment 3, wherein the viscosifier comprises at least one of carboxymethyl cellulose (CMC) or carrageenan. (5) The thickener-containing liquid composition according to embodiment 3 or 4, wherein the thickener comprises a mixture of at least two different thickener compounds.

[0080] (6) The thickener-containing liquid composition according to embodiment 5, wherein the thickener is a mixture of carboxymethyl cellulose (CMC) and carrageenan. (7) The thickener-containing liquid composition according to any one of embodiments 3 to 6, wherein the thickener is present in the composition in an amount in the range of about 0.1% to about 10% (w / v). (8) The liquid composition according to any one of embodiments 1 to 7, wherein the electrophilic compound comprises a PEG N-hydroxysuccinimide activated ester (PEG-NHS). (9) The liquid composition according to embodiment 8, wherein the PEG-NHS is a PEG-succinimidyl glutarate ester (PEG-SG). (10) The liquid composition according to any one of embodiments 1 to 9, wherein the nucleophilic compound comprises at least one of 4-arm PEG-amine or albumin.

[0081] (11) The liquid composition according to any one of embodiments 1 to 10, wherein the amphiphilic poly(alkyl) ethylene glycol block polymer comprises polyethylene glycol, polypropylene glycol, and basic units of these copolymers. (12) The liquid composition according to embodiment 11, wherein the amphiphilic poly(alkyl) ethylene glycol block polymer comprises a triblock copolymer containing a central block of polypropylene glycol and two terminal blocks of polyethylene glycol (PEG). (13) The liquid composition according to any one of embodiments 1 to 12, wherein the amphiphilic poly(alkyl) ethylene glycol block polymer is in the range of about 5% to about 15% (w / v) of the sealant composition. (14) The liquid composition according to embodiment 13, wherein the amphiphilic poly(alkyl) ethylene glycol block polymer is in the range of about 7.5% to about 12.5% (w / v) of the sealant composition. (15) A system for forming a crosslinkable soft tissue sealant, comprising: A first container containing a first liquid, wherein the first liquid has a buffer solution having a pH in the range of about 8.5 to about 9.0, a crosslinkable electrophilic compound, and an amphiphilic poly(alkyl) ethylene glycol block polymer; a first container; A second container containing a second liquid, wherein the second liquid has a buffer solution having a pH in the range of about 8.5 to about 9.0 and a crosslinkable nucleophilic compound; a second container; The crosslinkable electrophilic compound and the crosslinkable nucleophilic compound are configured to form a crosslinked soft tissue sealant upon mixing of the first liquid and the second liquid. A system.

[0082] (16) The system according to embodiment 15, wherein the first container further comprises a thickening agent. (17) The system according to embodiment 16, wherein the thickening agent comprises at least one of carboxymethyl cellulose (CMC) or carrageenan. (18) The system according to embodiment 16 or 17, wherein the thickening agent is present in the composition in an amount in the range of about 0.1% to about 10% (w / v). (19) The system according to any one of embodiments 15 to 18, wherein the amphiphilic poly(alkyl) ethylene glycol block polymer comprises basic units of polyethylene glycol, polypropylene glycol, and copolymers thereof. (20) The system according to embodiment 19, wherein the amphiphilic poly(alkyl) ethylene glycol block polymer comprises a triblock copolymer comprising a central block of polypropylene glycol and two terminal blocks of polyethylene glycol (PEG).

[0083] (21) The system according to any one of embodiments 15 to 20, wherein the amphiphilic poly(alkyl) ethylene glycol block polymer is in the range of about 5% to about 15% (w / v) of the sealant composition. (22) The amphiphilic poly(alkyl) ethylene glycol block polymer is in the range of about 7.5% to about 12.5% (w / v) of the sealant composition, the system according to embodiment 21. (23) A method for treating or repairing soft tissue, mixing a first liquid contained in a first container and a second liquid contained in a second container to form a liquid soft tissue sealant, wherein the first liquid is a buffer solution having a pH in the range of about 8.5 to about 9.0, a crosslinkable electrophilic compound, and an amphiphilic poly(alkyl) ethylene glycol block polymer, and the second liquid is a buffer solution having a pH in the range of about 8.5 to about 9.0 and a crosslinkable nucleophilic compound, forming; forming a liquid tissue sealant from the mixture of the first and second fluids; applying the liquid tissue sealant to cover the target pleural tissue surface; crosslinking the liquid tissue sealant on the target pleural tissue surface; comprising the method. (24) A liquid composition for forming a crosslinked sealant for expandable soft tissue, a reactive hydrogel mixture comprising a multi-arm polyethylene glycol (PEG)-based polymer having at least one reactive electrophilic group and a multi-arm polymer containing at least one reactive amine group; an amphiphilic poly(alkyl) ethylene glycol block polymer in an amount of 20% (w / v) or less of the liquid composition; a thickener in the range of about 0.1% to about 10% (w / v); a buffer solution having a pH in the range of about 8.5 to about 9.0; consisting essentially of, when measured against a comparative liquid composition having the reactive hydrogel mixture and the buffer solution in the absence of the amphiphilic poly(alkyl) ethylene glycol block polymer, the liquid composition has, after crosslinking, a greater ultimate elongation value and ultimate stress value than the crosslinked comparative liquid composition measured under the same conditions.

Claims

**Claim 1** A liquid composition for forming a crosslinkable soft tissue sealant, a reactive hydrogel mixture comprising an electrophilic compound and a nucleophilic compound, wherein the electrophilic compound comprises a multi-arm polyethylene glycol (PEG)-based polymer, the nucleophilic compound comprises at least one reactive amine group, and the electrophilic compound and the nucleophilic compound are crosslinkable with each other via the reaction of the available electrophilic and nucleophilic moieties of each compound, a reactive hydrogel mixture; an amphiphilic poly(alkyl) ethylene glycol block polymer in an amount of 20% (w / v) or less of the sealant composition; and a buffer solution having a pH in the range of about 8.5 to about 10.5, wherein the composition has a final crosslinked hydrogel phase having an ultimate elongation in the range of about 15 mm to about 40 mm and an ultimate tensile stress in the range of about 2.4 kPa to 5.9 kPa. A liquid composition. **Claim 2** The liquid composition according to claim 1, wherein the buffer solution has a pH in the range of about 8.5 to about 9.

0. **Claim 3** The liquid composition according to claim 1 or 2, further comprising a thickening agent. **Claim 4** The liquid composition according to claim 3, wherein the thickening agent comprises at least one of carboxymethyl cellulose (CMC) or carrageenan. **Claim 5** The liquid composition according to claim 3, wherein the thickening agent comprises a mixture of at least two different thickening agent compounds. **Claim 6** The liquid composition according to claim 5, wherein the thickening agent is a mixture of carboxymethyl cellulose (CMC) and carrageenan. **Claim 7** The liquid composition according to claim 3, wherein the thickening agent is present in the composition in an amount in the range of about 0.1% to about 10% (w / v). **Claim 8** The liquid composition according to claim 1, wherein the electrophilic compound comprises PEG N-hydroxysuccinimide activated ester (PEG-NHS). **Claim 9** The liquid composition according to claim 8, wherein the PEG-NHS is PEG-succinimidyl glutarate ester (PEG-SG). **Claim 10** The liquid composition according to claim 1, wherein the nucleophilic compound comprises at least one of 4-arm PEG-amine or albumin. **Claim 11** The liquid composition according to claim 1, wherein the amphiphilic poly(alkyl) ethylene glycol block polymer comprises polyethylene glycol, polypropylene glycol, and the basic units of copolymers thereof. **Claim 12** The liquid composition according to claim 11, wherein the amphiphilic poly(alkyl) ethylene glycol block polymer comprises a triblock copolymer including a central block of polypropylene glycol and two terminal blocks of polyethylene glycol (PEG).

13. The liquid composition according to claim 1, wherein the amphiphilic poly(alkyl) ethylene glycol block polymer is in the range of about 5% to about 15% (w / v) of the sealant composition.

14. The liquid composition according to claim 13, wherein the amphiphilic poly(alkyl) ethylene glycol block polymer is in the range of about 7.5% to about 12.5% (w / v) of the sealant composition.

15. A system for forming a crosslinked sealant for expandable soft tissue, comprising: a first container containing a first liquid, the first liquid having a buffer solution with a pH in the range of about 8.5 to about 9.0, a crosslinkable electrophilic compound, and an amphiphilic poly(alkyl) ethylene glycol block polymer, the first container; a second container containing a second liquid, the second liquid having a buffer solution with a pH in the range of about 8.5 to about 9.0 and a crosslinkable nucleophilic compound, the second container; The system, wherein the crosslinkable electrophilic compound and the crosslinkable nucleophilic compound are configured to form a crosslinked soft tissue sealant when the first liquid and the second liquid are mixed.

16. The system according to claim 15, wherein the first container further comprises a thickening agent.

17. The system according to claim 16, wherein the thickening agent comprises at least one of carboxymethyl cellulose (CMC) or carrageenan.

18. The system according to claim 16 or 17, wherein the thickening agent is present in the composition in an amount in the range of about 0.1% to about 10% (w / v).

19. The system according to claim 15, wherein the amphiphilic poly(alkyl) ethylene glycol block polymer comprises polyethylene glycol, polypropylene glycol, and basic units of these copolymers.

20. The system according to claim 19, wherein the amphiphilic poly(alkyl) ethylene glycol block polymer comprises a triblock copolymer including a central block of polypropylene glycol and two terminal blocks of polyethylene glycol (PEG).

21. The system according to claim 15, wherein the amphiphilic poly(alkyl) ethylene glycol block polymer is in the range of about 5% to about 15% (w / v) of the sealant composition.

22. The system according to claim 21, wherein the amphiphilic poly(alkyl) ethylene glycol block polymer is in the range of about 7.5% to about 12.5% (w / v) of the sealant composition.

23. A method for treating or repairing soft tissue, comprising mixing a first liquid contained in a first container and a second liquid contained in a second container to form a liquid soft tissue sealant, wherein the first liquid comprises a buffer solution having a pH in the range of about 8.5 to about 9.0, a crosslinkable electrophilic compound, and an amphiphilic poly(alkyl) ethylene glycol block polymer, and the second liquid comprises a buffer solution having a pH in the range of about 8.5 to about 9.0 and a crosslinkable nucleophilic compound, forming; forming a liquid tissue sealant from the mixture of the first and second fluids; applying the liquid tissue sealant to cover a target pleural tissue surface; crosslinking the liquid tissue sealant on the target pleural tissue surface; A method comprising the steps of.

24. A liquid composition for forming a crosslinked sealant for expandable soft tissue, a reactive hydrogel mixture comprising a multi-arm polyethylene glycol (PEG)-based polymer having at least one reactive electrophilic group and a multi-arm polymer containing at least one reactive amine group; an amphiphilic poly(alkyl) ethylene glycol block polymer in an amount of 20% (w / v) or less of the liquid composition; a thickening agent in the range of about 0.1% to about 10% (w / v); a buffer solution having a pH in the range of about 8.5 to about 9.0; essentially consisting of; When measured against a comparative liquid composition having the reactive hydrogel mixture and the buffer solution in the absence of the amphiphilic poly(alkyl) ethylene glycol block polymer, the liquid composition has an ultimate elongation value and an ultimate stress value greater than those of the crosslinked comparative liquid composition measured under the same conditions after crosslinking. A liquid composition.

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