Flowable hydrogel colloid composite sealant

Abstract

Provided herein are hydrogel-hydrocolloid sealant compositions for use as soft tissue sealants. The composition may include a crosslinkable electrophilic component; a cross-linkable nucleophilic component; comprising gelatin; and a buffer having a pH in the range of about 9.0 to about 10.0. The composition may have a first fluid state and a second cross-linked state, and in the cross-linked state, the electrophilic component and the nucleophilic component are cross-linkable to form a cross-linked hydrogel network in which the swellable filler material comprising gelatin is disposed within the cross-linked network. Systems and methods of making the sealant compositions and methods of repairing soft tissue defects comprising administering the sealant compositions disclosed herein are also provided.

Description

Technical Field

[0001] The present disclosure relates to crosslinked hydrogel - hydrocolloid sealant compositions, as well as manufacturing systems and methods therefor. The present disclosure further describes methods of treatment using these compositions. Background Art

[0002] Image - guided percutaneous transthoracic needle biopsy (PTNB) is an established procedure for patients with a suspected pathologic process such as bronchogenic carcinoma. The purpose of this procedure is to obtain tissue for cytologic or histologic examination. This procedure is typically performed by a radiologist under image guidance. The imaging modalities utilized include fluoroscopy, computed tomography (CT), and ultrasound. Ultrasound is the safest, fastest, and least expensive method; however, it is only useful for very superficial samples. When the lesion is not suitable for ultrasound examination, CT is the preferred imaging modality.

[0003] PTNB is classified according to the type of needle. Fine - needle aspiration biopsy is performed to provide cytologic specimens, while larger - diameter cutting needles are used to produce histologic specimens. Historically, the complication rate of cutting needles was relatively high, but with the introduction of automated cutting needles, recent studies have shown that the complication rates of fine - needle aspiration and cutting needles are comparable.

[0004] During PTNB, an aspiration needle (18 - 22 gauge) or a cutting needle (14 - 20 gauge) is placed under image guidance for sample retrieval. Coaxial techniques can be used to allow multiple passes within the pulmonary tract and reduce the number of pleural punctures. In this technique, a thin - walled guide needle (13 - 19 gauge) is first inserted and positioned at the lesion, and then the aspiration or cutting needle is inserted.

[0005] Although this procedure is considered safe and effective, the incidence of pneumothorax remains high, ranging from 12% to 61%, with 2% to 15% requiring chest tube drainage. If the lesion is not close to the pleura, the risk of pneumothorax increases significantly. Most complications occur immediately after the biopsy or within the first hour after the biopsy. Therefore, after the procedure, the patient is placed in a position with the puncture site downward and kept under supervision for at least 1 hour. Patients may experience shortness of breath, chest pain, and hypoxia. Most pneumothoraces with acute symptoms can be detected by chest radiograph. Oxygen is administered to patients with observed pneumothorax to accelerate the reabsorption of the pneumothorax.

[0006] Transbronchial needle aspiration (TBNA) is a minimally invasive technique that allows sampling of mediastinal lymph nodes. When combined with endobronchial ultrasound (EBUS), it enables precise definition of mediastinal structures. Modern devices integrate an ultrasound bronchoscope into the needle, allowing real-time visualization of the area of interest. The diagnostic rate of EBUS-TBNA in lung cancer screening has been reported to have a sensitivity as high as 95.7%. Therefore, EBUS-TBNA is being widely adopted as the standard of care for mediastinal lymph node sampling.

[0007] The EBUS device consists of a transducer and a processor. The transducer generates sound waves and receives them. The processor integrates the reflected sound to generate an image. The probe includes a balloon that can be inflated to improve contact with the airway. The EBUS-TBNA device includes an ultrasound linear processing array and a retractable needle. EBUS-TBNA was initially performed with a dedicated 22-gauge aspiration needle; however, a larger 21-gauge needle has recently been introduced. EBUS-TBNA is performed in the proximal lumen of the 9th-order bronchi because they are limited by the outer diameter of the bronchoscope (6.9 mm). Although the complications of EBUS-TBNA are very low, the incidence of pneumothorax remains high. After EBUS-TBNA, the incidence of pneumothorax is estimated to be 0.53% to 16.7%.

[0008] In most institutions worldwide, there is still a lack of standardized strategies for the choice between TBNA or PTNB. This choice is usually influenced by environmental factors such as operator experience or institutional resources. There is no established algorithm based on clinical scenarios. However, PTNB is generally preferred for lesions near the visceral pleura, while TBNA is preferred for lesions near the airway.

[0009] Patients who are observed to have an expanding pneumothorax must be treated by placing a chest tube. However, there is no universally accepted method to reduce the pneumothorax rate. Multiple solutions have been employed to reduce the incidence of pneumothorax. Several authors have studied techniques to reduce the incidence of pneumothorax, including rapid rollover and deep exhalation and breath-holding techniques, but these techniques have only shown mild / moderate effects, with a risk reduction of 0.1% - 15.7%.

[0010] Therefore, others have studied the perfusion of various sealant materials into the lung tract, including autologous blood clots, fibrin glue, and gelatin foam, but none of them have been widely used in daily practice. These methods have also been affected by variable results, probably as a result of operator dependence and variations in practice. Autologous blood clots have shown moderate efficacy but have the problem of long operating room preparation time. Although fibrin glue and gelatin techniques have demonstrated some promising published data, they have not been widely studied.

[0011] Liquid synthetic sealants, such as those derived from reactive polyethylene glycols (examples: PEG-amine and PEG-succinimidyl glutarate (SG)) or biological sealants (example: fibrin sealant) are only likely to effectively seal lung tissue ducts if they can crosslink sufficiently without interference. Although this would theoretically result in significant adhesive strength (via covalent crosslinking and / or mechanical interlocking and cohesive strength), the positive pressure of the lung encountered during surgery in combination with the low density and viscosity of the liquid sealant causes the sealant to not fully crosslink. The sealant will be affected by the expulsion of air from the duct and / or unintentional foaming, which creates a path of least resistance, resulting in its inability to seal air leaks.

[0012] Recently, synthetic polyethylene glycol embolization materials have been developed as part of the BioSentry duct sealant system (hemodynamics). In a randomized multicenter clinical trial, BioSentry resulted in 85% of patients being free of pneumothorax, which was statistically greater than the control group (69%). However, the solid nature of the embolization material induced a foreign body giant cell reaction and encapsulation of the hydrogel within only 21 days (see the figure below). More porous embolization materials would cause a reduced foreign body reaction and faster healing.

[0013] WO 2008 / 016983 relates to a wound sealing composition that comprises a first crosslinkable component and a second crosslinkable component and at least one hydrogel-forming component. The composition may also comprise a fast-acting material, such as a tissue sealant, and the composition exhibits minimal swelling characteristics. The first crosslinkable component and the second crosslinkable component may each be, for example, polyethylene glycol, and the hydrogel-forming component may be, for example, gelatin, which may comprise subunits having dimensions in the range of about 0.01 mm to about 5 mm when fully hydrated and having an equilibrium swelling in the range of about 400% to about 5000%. The first component and the second component react under in vivo conditions to form a crosslinked matrix, while the hydrogel-forming component rapidly absorbs biological fluids flowing out through a tissue tear and enhances the resulting physical sealant matrix barrier formed when the first component and the second component crosslink.

[0014] Accordingly, there is a need in the art for improved sealant compositions that can effectively seal pleural ducts. Summary of the Invention

[0015] The present disclosure describes a hydrogel-hydrocolloid expandable soft tissue sealant composition that comprises a crosslinkable electrophilic component; a crosslinkable nucleophilic component; a swellable filler material including gelatin; and a buffer having a pH in the range of about 9.0 to about 10.0. The sealant includes a first fluid state and a second crosslinked state, and in the crosslinked state, the electrophilic component and the nucleophilic component crosslink to form a crosslinked hydrogel network, and the swellable filler material including gelatin is disposed within the crosslinked network.

[0016] According to certain embodiments, the gelatin is a thermally crosslinked pre-wetted gelatin fluid or dry gelatin particles. In additional embodiments, the swellable filler material includes a blend of pre-wetted gelatin fluid and dry gelatin particles, and in further embodiments, the swellable filler material is present in the composition in an amount in the range of 50 mg / ml to about 10 mg / ml.

[0017] In still further embodiments, in the crosslinked state, the composition has a terminal bubble velocity, and the terminal bubble velocity of the crosslinked composition is at least 75% less than the terminal bubble velocity of a composition comprising an electrophilic component and a nucleophilic component in the absence of a swellable filler. In additional embodiments, the terminal bubble velocity of the crosslinked composition is at least 90% less than the terminal bubble velocity of a composition comprising an electrophilic component and a nucleophilic component in the absence of a swellable filler.

[0018] According to certain embodiments, the electrophilic component includes a multi-arm polyethylene glycol (PEG)-based polymer, and the nucleophilic component includes a multi-arm PEG polymer containing at least one reactive amine group. In further embodiments, the electrophilic component includes a PEG N-hydroxysuccinimide activated ester (PEG-NHS), such as PEG-succinimidyl glutarate (PEG-SG). In alternative embodiments, at least one of the crosslinkable electrophilic component and the crosslinkable nucleophilic component is a biocompound, including embodiments where both the crosslinkable electrophilic component and the crosslinkable nucleophilic component are biocompounds (such as where the electrophilic compound is thrombin and the nucleophilic compound is fibrinogen).

[0019] In still further embodiments, the sealant composition can have a crosslinked state, where the composition is a solid, and further, where the composition is lyophilized. In additional embodiments of the sealant composition, the swellable filler material is configured to expand in volume in the crosslinked state such that the composition has a crosslinked expandable state, and in this crosslinked expandable state, the composition is configured to provide a fluid-impermeable seal at a pressure differential of up to 25 cm of water.

[0020] The present disclosure also describes a system for forming a hydrogel - hydrocolloid expandable soft tissue sealant, the system comprising: a first container containing a cross - linkable electrophilic component; a second container containing a cross - linkable nucleophilic component; and a swellable filler material comprising gelatin, wherein the swellable filler material is disposed in the first container, the second container, or both, and wherein the first container and the second container are configured to be connected in fluid communication with each other. The cross - linkable electrophilic component and the cross - linkable nucleophilic component are configured to form a cross - linked hydrogel network when mixed between the first container and the second container, and the swellable material is disposed within the cross - linked hydrogel network.

[0021] In certain embodiments, the swellable material is disposed in the first container, the swellable material is disposed in the second container, or the swellable material is disposed in each of the first container and the second container. In certain embodiments, the swellable material is a pre - wetted gelatin fluid, the swellable material is dry gelatin particles, or the swellable material comprises both a pre - wetted gelatin fluid and dry gelatin particles. In further alternative embodiments, both the first container and the second container contain a pre - wetted gelatin fluid; in yet further alternative embodiments, the first container contains a pre - wetted gelatin fluid and the second container contains dry gelatin particles; and in still further alternative embodiments, the first container contains dry gelatin particles and the second container contains a pre - wetted gelatin fluid.

[0022] According to the present disclosure, a method of repairing a soft tissue defect is described, the method comprising:

[0023] applying a hydrogel - hydrocolloid expandable sealant composition to the soft tissue defect, the composition comprising a first cross - linkable component, a second cross - linkable component, and a swellable filler material comprising gelatin;

[0024] wherein the soft tissue defect extends from an outer surface of the soft tissue to an inner surface of the soft tissue, and wherein the inner surface defines a void containing a fluid that exerts a positive pressure in a direction from the void to the outer surface; and

[0025] exposing the sealant composition to an aqueous fluid such that the composition will cross - link and swell, such that the composition will fluidly seal the defect by adhesion to the soft tissue surface and an expansion force across the soft tissue defect. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1A 、 Figure 1B and Figure 1C are graphical representations of the ultimate elongation, ultimate stress, and elastic modulus measurements, respectively, of the formulations according to the present disclosure;

[0027] Figure 2Graphical representation of terminal bubble rise velocity values for several samples of gelatin at different concentrations and types, mixed in a non-functional PEG solution;

[0028] Figure 3A 、 Figure 3B 、 Figure 3C and Figure 3D Flowcharts depicting several systems and methods for manufacturing a sealant composition according to the present disclosure; and

[0029] Figure 4 A comparison graph showing the swelling properties of two materials. DETAILED DESCRIPTION

[0030] In this document, unless otherwise specified, the terms "a" or "an" are used to include one or more than one, and the term "or" is used to mean non-exclusive "or". In addition, it should be understood that the wording or terms used herein, unless otherwise defined, are for descriptive purposes only and not for limitation. When expressing a range of values, another embodiment includes from one specific value and / or to other specific values. Similarly, when a value is expressed as an approximation with "about" in front, it should be understood that the specific value of the value constitutes another embodiment. All ranges include the end values and are combinable. In addition, references to values described in a range include each value within that range. It should also be understood that, for clarity, certain features of the invention described herein in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, the various features of the invention have been described for brevity in the context of a single embodiment and may also be provided separately or in any sub-combination.

[0031] As used herein, "biocompatible" means compatible with living tissue or a living system, non-toxic, harmless or non-physiologically reactive thereto, and does not thereby cause immune rejection.

[0032] As used herein, "bioabsorbable" or "resorbable" means capable of degrading in the body into smaller molecules, the size of which allows them to be transported into the bloodstream. Such degradation and transport gradually removes the material from the site of administration. For example, gelatin can be degraded by tissue proteolytic enzymes into absorbable smaller molecules, whereby when applied to tissue, gelatin is typically absorbed within about 4 to 6 weeks, and when applied to a bleeding surface or mucosa, gelatin typically liquefies within 2 to 5 days.

[0033] As used herein, "hemostasis" refers to the process of reducing or stopping bleeding. During hemostasis, three steps occur in rapid sequence. Vasospasm is the first response as the blood vessels constrict to reduce blood loss. In the second step, a platelet plug forms where platelets stick together to form a temporary seal over the break in the blood vessel wall. The third and final step is called coagulation or blood clotting. During coagulation, fibrin threads act as a "molecular glue" to reinforce the platelet plug. Thus, a hemostatic material or compound is capable of stimulating hemostasis.

[0034] As used herein, "pneumostasis" means delivering a material to lung tissue to close or seal one or more air leaks.

[0035] As used herein, "pre-wetted gelatin" refers to gelatin particles (e.g., SURGIFLO) in an aqueous solution that meet the specifications defined in the United States Pharmacopeia (e.g., USP 29).

[0036] As used herein, "dry gelatin" refers to dry gelatin particle powder (e.g., SURGIFOAM powder) that meets the specifications defined in the United States Pharmacopeia (e.g., USP 29).

[0037] As used herein, the phrase "consisting essentially of" is intended to limit the scope of a claim to include the recited components, compounds, substances, materials, or steps, and additionally to include any components, compounds, substances, materials, or steps that do not materially affect the basic characteristics of the claimed invention.

[0038] The present disclosure describes a hydrogel - hydrocolloid expandable soft tissue sealant composition that comprises a crosslinkable electrophilic component; a crosslinkable nucleophilic component; a swellable filler material including gelatin; and a buffer having a pH in the range of about 9.0 to about 10.0. The sealant includes a first fluid state and a second crosslinked state, and in the crosslinked state, the electrophilic component and the nucleophilic component crosslink to form a crosslinked hydrogel network, and the swellable filler material including gelatin is disposed within the crosslinked network.

[0039] Gelatin

[0040] Both pre-wetted gelatin particles and dry gelatin particles are made from absorbable gelatin sponges that meet the specifications of the United States Pharmacopeia (e.g., USP 29). The porous structure and degree of crosslinking of the sponge are measured by the water absorption rate and digestibility according to the USP method. For each type of particle, the sponge should absorb no less than 35 times its weight in water, and the average digestion time by pepsin should not exceed 75 minutes.

[0041] Pre-wetted gelatin particles are prepared by mechanically grinding a sponge into fine particles and mixing the particles with an aqueous solution (such as a saline solution). They can have a particle size D90 of less than 1000 microns. That is, 90% of the pre-wetted gelatin particles can have a diameter of less than 1000 microns. The degree of crosslinking in the pre-wetted gelatin particles is such that they have a digestion time measured by the USP digestibility test (such as referring to the USP 34 monograph) of more than 30 minutes but not more than 75 minutes. The pre-wetted gelatin particles have a higher degree of crosslinking than dry gelatin particles.

[0042] Dry gelatin particles are prepared by grinding a gelatin sponge. They can have a particle size D90 of less than 2000 microns. That is, 90% of the dry gelatin particles can have a diameter of less than 2000 microns. The degree of crosslinking in the dry gelatin particles is such that they have a digestion time measured by the USP digestion test of less than 30 minutes. When mixed with an aqueous solution, the dry gelatin particles have a higher degree of swelling (absorbing at least 35 times their own dry weight of liquid, as described in the USP 34 monograph) than the pre-wetted gelatin particles.

[0043] According to certain embodiments, the gelatin is thermally crosslinked. In further embodiments, the gelatin is pre-wetted gelatin fluid or dry gelatin particles. In additional embodiments, the swellable filler includes a blend of pre-wetted gelatin fluid and dry gelatin particles, and in further embodiments, the swellable filler is present in the composition in an amount in the range of 50 mg / ml to about 10 mg / ml.

[0044] In further embodiments, in the crosslinked state, the composition has a terminal bubble velocity (as defined below), and the terminal bubble velocity of the crosslinked composition is at least 75% less than the terminal bubble velocity of a composition comprising an electrophilic component and a nucleophilic component in the absence of the swellable filler. In additional embodiments, the terminal bubble velocity of the crosslinked composition is at least 90% less than the terminal bubble velocity of a composition comprising an electrophilic component and a nucleophilic component in the absence of the swellable filler.

[0045] According to certain embodiments, the electrophilic component includes a multi-arm polyethylene glycol (PEG)-based polymer, and the nucleophilic component includes a multi-arm PEG polymer containing at least one reactive amine group.

[0046] The electrophilic and nucleophilic reactive compounds forming the crosslinked structure of the hydrogel sealant are known in the art and can include synthetic polymers (such as multi-arm polyethylene glycol (PEG)-based polymers) and natural substances, as well as combinations thereof. Suitable multi-arm PEGs can include 2, 3, 4, 6, or 8 multi-arm PEGs.

[0047] According to certain embodiments, the synthetic polymer may include polymers having activated esters, such as compound classes from PEG-N-hydroxysuccinimide (PEG-NHS), PEG-aldehyde, PEG-acrylate, carboxyl-PEG, and 4-arm vinyl-PEG. According to another embodiment, a non-exhaustive list of suitable electrophilic compounds may include 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-sulfo-succinimidyl glutarate (SG), 4-arm-PEG-sulfo-succinimidyl valerate, 4-arm-PEG-sulfo-succinimidyl carbonate, 4-arm-PEG-sulfo-succinimidyl succinate, 4-arm-sulfo-succinimidyl butyrate, 4-arm-PEG-sulfo-succinimidyl succinamide, 4-arm-PEG-sulfo-succinimidyl propionate, and 4-arm-PEG-isocyanate, 4-arm-PEG-imidate, 4-arm-PEG-maleimide, 4-arm-PEG-acetic acid, 4-arm-PEG-propionic 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.

[0048] As previously described, the electrophilic compound may also include a blend of natural and synthetic components.

[0049] In certain embodiments, the nucleophilic compound includes natural compounds such as albumin or fibrinogen. In certain additional embodiments, the nucleophilic compound may include synthetic polymers, preferably multi-arm polymers. In another 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.

[0050] In a preferred embodiment, the electrophilic component includes PEG N-hydroxysuccinimide activated ester (PEG-NHS), such as PEG-succinimidyl glutarate (PEG-SG). In an alternative preferred embodiment, at least one of the crosslinkable electrophilic component and the crosslinkable nucleophilic component is a biological compound, including embodiments where both the crosslinkable electrophilic component and the crosslinkable nucleophilic component are biological compounds (e.g., where the electrophilic compound is thrombin and the nucleophilic compound is fibrinogen).

[0051] In a further embodiment, the sealant composition can have a crosslinked state, where the composition is a solid and, further, where the composition is lyophilized. In additional embodiments of the sealant composition, the swellable filler material is configured to expand in volume in the crosslinked state such that the composition has a crosslinked swellable state, and in this crosslinked swellable state, the composition is configured to provide a fluid-impermeable seal at a water pressure differential of up to 30 cm.

[0052] The present disclosure also describes a system for forming a hydrogel-hydrocolloid swellable soft tissue sealant, the system comprising: a first container containing a crosslinkable electrophilic component; a second container containing a crosslinkable nucleophilic component; and a swellable filler material comprising gelatin, wherein the swellable filler material is disposed in the first container, the second container, or both, and wherein the first container and the second container are configured to be connected in fluid communication with each other. The crosslinkable electrophilic component and the crosslinkable nucleophilic component are configured to form a crosslinked hydrogel network when mixed between the first container and the second container, and the swellable material is disposed within the crosslinked hydrogel network.

[0053] In certain embodiments, the swellable material is disposed in the first container, the swellable material is disposed in the second container, or the swellable material is disposed in each of the first container and the second container. In certain embodiments, the swellable material is a pre-wetted gelatin fluid, the swellable material is dry gelatin particles, or the swellable material comprises both a pre-wetted gelatin fluid and dry gelatin particles. In additional embodiments, both the first container and the second container contain a pre-wetted gelatin fluid; in a further alternative embodiment, the first container contains a pre-wetted gelatin fluid and the second container contains dry gelatin particles; and in a still further alternative embodiment, the first container contains dry gelatin particles and the second container contains a pre-wetted gelatin fluid.

[0054] According to the present disclosure, a method of repairing a soft tissue defect is described, the method comprising:

[0055] administering a hydrogel-hydrocolloid swellable sealant composition to the soft tissue defect, the composition comprising a first crosslinking component, a second crosslinking component, and a swellable filler material comprising gelatin;

[0056] wherein the soft tissue defect extends from an outer surface of the soft tissue to an inner surface of the soft tissue, and wherein the inner surface defines a fluid-containing void, and the fluid exerts a positive pressure in a direction from the void to the outer surface; and

[0057] exposing the sealant composition to an aqueous fluid such that the composition will crosslink and swell such that the composition will fluidly seal the defect by adhesion to the soft tissue surface and an expansion force across the soft tissue defect.

[0058] Example

[0059] Example 1 - Effect of pH on the Preparation of Sealant Formulations

[0060] PEG Amine / Surgifoam Preparation

[0061] 5 mL of 114 mg / mL PEG-amine 4 - 5k was added to one unit of powder and distributed evenly by shaking the powder until a wet mass was formed. This was tested at two pH ranges of the PEG-amine formulation: [9.0 - 9.5] and [10.5 - 11]. When mixed with the PEG-amine solution, the powder formed a more liquid and softer paste at pH = 9.0 than at pH ≥ 9.5. The powder was easier to process at pH = 9.0. The samples were transferred to 20 mL Luer-lock syringes.

[0062] PEGSG / Surgiflo Preparation

[0063] 750 mg of PEG-SG 4 - 10k was dissolved in 5 mL of 100 mM carbonate buffer (pH = 9.0) for 5 minutes. The PEG-SG 4 - 10k was loaded into a 20 mL Luer-lock syringe and evenly dispensed into one unit using the dual-syringe exchange method.

[0064] pH: 10.5 / 11.0

[0065] Once the / PEG-amine components at pH = 10.5 and 11.0 were fully mixed with the

[0066] / PEG-SG components using the dual-syringe method through 20 passes, the sealant crosslinked inside the syringe before 2 passes were completed, so it was considered to crosslink too fast.

[0067] Once the / PEG-amine components at pH = 9.0 and 9.5 were fully mixed with the

[0068] Example 2 - Comparison of Tensile Properties of Thrombin - containing Surgiflo and Surgiflo with Reactive PEG Matrix

[0069] Formulation :

[0070] A. Thrombin - containing Surgiflo

[0071] Prepare thrombin-containing Surgiflo according to the Instructions for Use (IFU) approved by the FDA for the Surgiflo Hemostatic Matrix Kit. Connect a sterile water for injection syringe to the thrombin vial, add the entire volume of water for injection to the thrombin vial, and mix with the thrombin until a clear solution is formed. Withdraw all of the contents of the solution from the thrombin vial and into the syringe using the attached syringe. Store the contents of the syringe in a sterile transfer cup for further use. Withdraw 2 mL of the thrombin solution into a new sterile syringe, connect this syringe to the pre-filled gelatin syringe, and mix the contents between the two syringes approximately six times.

[0072] B. Surgiflo Containing PEG - SG and PEG - Amine [pH = 9.0]

[0073] Mix 2.5 mL of PEG-amine in 50 mM carbonate buffer (pH = 9.9) at 228 mg / mL with one unit of Surgiflo by passing the two components back and forth 10 times. Transfer the suspension to a 20 mL syringe and remove all air. Add 2.5 mL of 50 mM carbonate buffer (pH = 9.0) to 750 mg of PEG-SG to obtain a PEG-SG concentration of 300 mg / mL. Dissolve the PEG-SG by gentle inversion and allow it to dissolve for 5 minutes. Once dissolved, transfer the PEG-SG solution to a 20 mL syringe and remove all air. Mix the PEG-SG solution with the Surgiflo / PEG-amine solution by passing the two components back and forth 8 times using the double-syringe method. Immediately inject the sealant into a tensile mold for testing.

[0074] Tensile testing measures the elongation at which the sealant completely fails when tested at 5 mm / min in the vertical tensile direction. Apply the sealant to a custom "dogbone" fixture and allow it to fully cure. Once cured, test the sample in a uniaxial tensile test using an Instron tensile testing machine at a rate of 5 mm / min. As Figure 1A shown, the ultimate elongation of PEG-containing Surgiflo is significantly 127 times greater than that of thrombin-containing Surgiflo.

[0075] As Figure 1B shown, the ultimate stress of PEG-containing Surgiflo is significantly 28 times greater than that of thrombin-containing Surgiflo.

[0076] As Figure 1C shown, the elastic modulus of PEG-containing Surgiflo is moderately reduced relative to thrombin-containing Surgiflo.

[0077] In these tests, Surgiflo with thrombin was used as the negative control because the formulation did not have the expected cohesive strength in the absence of blood. Thus, Surgiflo with thrombin was used as the baseline to demonstrate that the addition of PEG was the cause of the cohesive strength of the sealant formulation.

[0078] Example 3 - Viscosity of Gelatin - PEG Composite Flowable Sealant

[0079] The purpose of this study was to determine the effect of adding gelatin to a synthetic poly(ethylene glycol)-based sealant. In ex vivo and in vivo studies, it was observed that adding Surgiflo and Surgifoam gelatin to the PEG in-situ crosslinking sealant improved the ability of the sealant to resist extrusion from the site of the pulmonary conduit defect. The ability to resist extrusion can be evaluated by analyzing the bubble rise viscosity of the leaking air in the pulmonary conduit. The terminal bubble rise viscosity (u ∞ ) is described by the following formula:

[0080]

[0081] where g is the acceleration due to gravity, d e is the equivalent bubble diameter, μ l is the dynamic viscosity of the sealant, ρ l is the density of the sealant, and ρ g is the density of the gas.

[0082] Material :

[0083] Sodium carbonate, σS7795, lot number: BCCB0812

[0084] Non-functional PEG, 4-arm, 20 kDa, Jenkem, lot number: LP2005R-191101

[0085] Method :

[0086] In this study, non-functional PEG was used as a model compound for PEG-SG and PEG-amine to avoid gelation during the measurement process. 124 mg / mL of non-functional PEG was dissolved in 100 mM carbonate buffer (pH = 9.0). 5 mL of PEG was mixed with 1 unit of Surgiflo by 10 passes using a dual-syringe exchange method. The Surgiflo / PEG mixture was serially diluted 1:2 using a dual-syringe exchange method to obtain 50%, 25%, and 12.5% units of Surgiflo in PEG. 5 mL of PEG mixture was added to 1 unit of Surgifoam powder by vigorously shaking the provided container. The Surgifoam / PEG mixture was serially diluted 1:2 using a dual-syringe exchange method to obtain 50%, 25%, and 12.5% units of Surgiflo in PEG.

[0087] The 100% Surgiflo / PEG and 100% Surgifoam / PEG mixtures were combined in equal ratios to obtain a 100% Surgifoam / PEG mixture. The Surgiflo / Surgifoam / PEG mixture was serially diluted 1:2 using a dual-syringe exchange method to obtain 50%, 25%, and 1.55% units of Surgiflo / Surgifoam in PEG. Note: These concentrations are the sum of Surgiflo and Surgifoam: the concentration of each component is half of the total gelatin concentration.

[0088] The composite mixtures were tested using a rheometer under a controlled rate rotation setting. The temperature was kept constant at 24 °C. 1 mL of the sample was added and the crosshead was lowered at 100 / s. After a 2-minute temperature preconditioning, the viscosity was measured in 10 linear steps from 100 / s to 1000 / s.

[0089] The density was calculated based on the values shown below.

[0090] Table 1

[0091] Sample Density (g / mL) 124 mg / mL Non - functional PEG 1.124 Surgiflo 0.7 Surgifoam Powder 1.52

[0092] Result :

[0093] The density calculations, viscosity data, and resulting relative terminal bubble velocities are shown in the table below.

[0094] Table 2

[0095]

[0096]

[0097] The terminal bubble velocity data was fitted to an exponential curve according to the following formula:

[0098] Surgiflo U ∞ = 1.0054e -4.2195*[Surgiflo]

[0099] Surgifoam U ∞ = 0.9970e -11.9319*[Surgifoam]

[0100] Surgiflo / Surgifoam U ∞ = 0.9999e -10.2123*[Surgiflo / Surgifoam]

[0101] Using Figure 2 the curve fitting shown in

[0102] Table 3

[0103]

[0104] the concentration at which the terminal bubble rise velocity is reduced by one order of magnitude was determined. The minimum concentrations corresponding to 90% and 75% reduction are shown in the table below. The viscosity of the solution is the main factor determining the bubble rise velocity. The minimum concentrations of 54.6% units of Surgiflo, 19.3% units of Surgifoam, and 22.5% units of Surgiflo / Surgifoam (or 11.25% each) per 5 mL of sealant increase the sealant's ability to resist air bubble extrusion by 90%. The minimum concentrations of 32.9% units of Surgiflo, 11.6% units of Surgifoam, and 13.6% units of Surgiflo / Surgifoam (or 6.8% each) per 5 mL of sealant increase the sealant's ability to resist air bubble extrusion by 75%.

[0105] Example 4 - In - situ Solidifying Gelatin Paste Hydrogel / Hydrocolloid Composite

[0106] Materials: 2 units of 2.5 mL of 4-arm PEG-SG at 300 mg / mL, molecular weight 20k (pH = 9.0), and 2.5 mL of 4-arm PEG-amine at 228 mg / mL, molecular weight 5k (pH = 11.0).

[0107] Preparation Method

[0108] 2.5 mL of 228 mg / mL 4-arm PEG-amine-5k (pH = 11.0) was added to 1 unit of In it, and use the double-syringe exchange method to blend through at least 6 transfers. There is a high pH of PEG-amine to accelerate crosslinking.

[0109] Add 2.5 mL of 300 mg / mL 4-arm PEG-SG-20k (pH = 9.0) [Note: The pH of PEG-SG cannot be changed in the same way because it will cause undesirable hydrolysis of the SG group, resulting in a decrease in the activity of the crosslinking agent] to 1 unit of In it, and use the double-syringe exchange method to blend through at least six transfers.

[0110] When in use, - PEG-amine dispersion and - PEG-SG dispersion can be combined via the double-syringe exchange method through 8 transfers. The sealant has a working time of approximately 20 seconds.

[0111] Sealing Method

[0112] The sealant can be applied using a typical Applicator tip and crosslinked within 20 seconds.

[0113] The fluidity allows for good conformity to the tube. The viscosity, density, and rapid crosslinking of the sealant prevent the sealant from being disturbed by positive pulmonary pressure during ventilation.

[0114] Noteworthy regarding this particular formulation is that this embodiment requires high concentrations of PEG-SG and PEG-amine to reduce the water content of the formulation. When tested at lower concentrations, the formulation has an ineffective liquid consistency.

[0115] Example 5 - In - situ Solidifying Hydrogel / Hydrocolloid Using Gelatin Paste / Powder Blend

[0116] Materials: 1 unit of 1 unit of Powder, 5 mL of 150 mg / mL 4-arm PEG-SG-20k (pH = 9.0), and 5 mL of 114 mg / mL 4-arm PEG-amine-5k (pH = 9.0).

[0117] Preparation Method

[0118] Add 5 mL of 114 mg / mL 4-arm PEG-amine-5k (pH = 9.0) to The powder, and incorporate it into the powder by vigorously shaking the powder container. Time should be provided to allow the PEG-amine to adsorb onto the gelatin particles via hydrophobic interactions. PEG-amine / The powder mixture forms material spheres. Remove the plunger from syringe 1, transfer the material spheres to syringe 1, and reinstall the plunger.

[0119] Syringe 2 is filled with 5 mL of 4-arm PEG-SG-20k (pH = 9.0) at 150 mg / mL. Syringe 3 is filled with 1 unit of Syringes 2 and 3 are mixed via a dual-syringe exchange method by 6 passes. Syringe 4 is filled with a mixture of PEG-SG and .

[0120] Syringes 1 and 4 are mixed together to activate the sealant via the dual-syringe method by 8 passes. The sealant has a working time of 2 minutes. The sealant has an approximate working time of 2 minutes.

[0121] Sealing Method

[0122] The sealant can be applied using a typical applicator tip and crosslinked within 2 minutes. The powder enables the sealant to swell and increases the viscosity. The viscosity and density of the sealant prevent the sealant from being disturbed by positive pulmonary pressure during ventilation. The longer working time allows for packing while the sealant swells and crosslinks.

[0123] Example 6: In - situ Solidifying Fibrin / Gelatin Composite

[0124] Materials: 1 unit of and 1 unit of powder, 5 mL of Evicel fibrinogen, and 5 mL of Evicel thrombin.

[0125] Preparation Method

[0126] In container 1, 5 mL of Evicel fibrinogen is admixed with 1 unit of powder via vigorous shaking. Time should be provided to allow the fibrinogen to physically interact with the gelatin. The fibrinogen will form a monolayer surrounding the gelatin particles. The fibrinogen / powder mixture forms a material ball. The plunger is removed from syringe 1, the material ball is transferred to syringe 1, and the plunger is reinstalled. Syringe 2 is filled with 5 mL of Evicel thrombin. Syringe 3 is filled with 1 unit of Syringes 2 and 3 are mixed via a dual-syringe exchange method by 6 passes. Syringe 4 is filled with a mixture of thrombin and . Syringes 1 and 4 are mixed together to activate the sealant via the dual-syringe method by 8 passes. The sealant has a working time of 30 seconds.

[0127] In use, the fibrinogen-soaked powder can be rolled into a ball and manually transferred to a 20 mL syringe. Then - The thrombin dispersion and the fibrinogen-soaked powder are mixed by 10 passes via a dual-syringe exchange method. The sealant has a working time of approximately 30 seconds (Note: Typically, fibrin sealants have a working time of less than 5 seconds).

[0128] Sealing Method

[0129] For use, the fibrinogen-soaked powder can be rolled into a ball and manually transferred into a 20 mL syringe. Then - The thrombin dispersion and the fibrinogen-soaked powder are mixed by 10 passes via a dual-syringe exchange method. The sealant can be applied using a typical applicator tip and crosslinked within 30 seconds. The viscosity and density of the sealant can prevent the sealant from being disturbed by positive pulmonary pressure during ventilation.

[0130] The resulting embolism is a thick paste, which can fit well into the defect when using a packing material, and has toughness, elasticity and compressibility after crosslinking. The powder provides a scaffold for the formation of fibrinogen, enables the sealant to swell, and increases the viscosity.

[0131] As a result of the interaction between fibrinogen and the powder before use, the gelatin powder physically interacts with the fibrin network. Another potential benefit of this formulation is that when the sealant is exposed to bleeding and endogenous fibrin formation, the sealant will become further stabilized.

[0132] Example 7 - In - situ Solidifying Fibrin / Gelatin Composite (Low Extrusion Force Formulation)

[0133] Materials: 1 unit of 1 unit of powder, 5 mL Evicel fibrinogen and 5 mL Evicel thrombin.

[0134] Preparation Method

[0135] To prepare a sealant that requires a lower extrusion force, 5 mL of Evicel thrombin is admixed with 1 unit of powder in container 1 via vigorous shaking. The thrombin / powder mixture forms a ball of material. The plunger is removed from syringe 1, the ball of material is transferred into syringe 1, and the plunger is reinstalled. Syringe 2 is filled with 5 mL of Evicel fibrinogen. Syringe 3 is filled with 1 unit of Syringe 2 and 3 are mixed by 6 passes via the dual-syringe exchange method. Syringe 4 is filled with fibrinogen and The mixture. Syringes 1 and 4 are mixed together to activate the sealant via the dual-syringe method with 8 passes. The sealant has a working time of 30 seconds.

[0136] In use, the thrombin-soaked powder can be rolled into a ball and manually transferred to a 20 mL syringe. Then the - fibrinogen dispersion is mixed with the thrombin-soaked powder via the dual-syringe exchange method with 10 passes. The sealant has a working time of approximately 30 seconds (Note: Typically, fibrin sealants have a working time of less than 5 seconds).

[0137] The resulting embolism is a thick paste that conforms well to the defect during application of packing and has toughness, elasticity, and compressibility after crosslinking.

[0138] Sealing Method

[0139] The sealant can be applied using a typical applicator tip and crosslinked within 30 seconds. The viscosity and density of the sealant prevent the sealant from being disturbed by positive pulmonary pressure during ventilation.

[0140] Compared to the second embodiment, the sealant produced in this embodiment requires less extrusion force for mixing using the dual-syringe method. The sealant has similar fluidity, consistency, and working time.

[0141] Example 8 - Dehydrated Sealant Formulation

[0142] Materials: 1 unit of 1 unit of powder, 5 mL of 150 mg / mL 4-arm PEG-SG-20k, and 5 mL of 114 mg / mL 4-arm PEG-NH2-5k, in 100 mM carbonate (pH = 9.0).

[0143] Preparation Method

[0144] 5 mL of 114 mg / mL 4-arm PEG-amine-5k (pH = 9.0) is added to the powder and incorporated into the powder by vigorously shaking the powder container. Time should be allowed for the PEG-amine to adsorb onto the gelatin particles via hydrophobic interactions.

[0145] 5 mL of 150 mg / mL PEG-SG-20k (pH = 9.0) is added to via the dual-syringe exchange method with at least 6 passes.

[0146] the - PEG-amine dispersion and The -PEG-SG dispersion can be combined via a dual-syringe exchange method by 10 passes and extruded into a cylindrical mold with a diameter of 0.41 mm to 1.8 mm.

[0147] The formulation was frozen at -80 °C for 1 hour, then lyophilized and released from the mold. The resulting embolic material was firm and resilient and could be used to seal the tract of a lung biopsy.

[0148] Sealing Method

[0149] After a lung biopsy procedure via a guiding needle, the dehydrated embolic material can be inserted into the tract. The embolic material rehydrates from the surrounding tissue fluid and (if desired) saline. When rehydrated, the powder enables the embolic material to swell.

[0150] Example 9: Comparison of Gelatin and Collagen as Swellable Fillers

[0151] The aim of this study was to evaluate the swelling of collagen and gelatin composite hydrogels. In some applications, swelling is a favorable property that can help seal large leaks. It is known that Surgiflo gelatin swells up to 35 times its original weight in blood, while collagen only swells up to about 2 times its original weight. In this study, collagen and gelatin were compared as swellable components of cross-linked PEG-based composite hydrogels in terms of swelling. As Figure 4 shown, the Surgiflo formulation swelled on average more than twice that of Instat (the collagen formulation) (225.7% vs 107.7%). There was a significant difference in swelling (p < 0.01).

[0152] Example 10: Ex - vivo Pressure Test

[0153] The ability of two sample formulations (one sample prepared according to Example 5 and one sample prepared according to Example 6) to achieve pneumothorax in an ex vivo porcine large lung tract model was evaluated.

[0154] In this model, fresh lung specimens were harvested on the day of testing and kept moist prior to testing. Prior to testing, the lungs were placed on a ventilator to recruit collapsed alveoli (the aim was to open collapsed airless alveoli). At the time of testing, the lungs were connected to a Respironics ventilator to precisely control the pressure during the ventilation cycle. The pressure was set at an inspiratory pressure of 25 cm water and an expiratory pressure of 5 cm water (Δ20 cm water).

[0155] A lung defect was created using a core device with a diameter of 18 mm, and the resulting puncture size was approximately 20 mm in diameter and 3 cm deep. The leakage at the defect was evaluated as severe by a bubble test. When applying the sample, the pressure was reduced to an inspiratory pressure of 10 cm of water and an expiratory pressure of 10 cm of water (no change) to maintain lung expansion.

[0156] After applying the sample, local compression was typically performed at the site of the sealant on the lung surface for 1 minute while the lung remained expanded and under positive pressure. To test performance, ventilation of the lung was started at low pressure and increased to an inspiratory pressure of 25 cm of water and an expiratory pressure of 5 cm of water (Δ20 cm of water). The bubble test was performed by passing saline through the puncture site and recording the presence and severity of leakage. For another challenge, the ventilation pressure was increased to an inspiratory pressure of 40 cm of water and an expiratory pressure of 5 cm of water (Δ35 cm of water).

[0157] Result

[0158] / PEG liquid sealant combination (Example 5). The components were mixed using a dual syringe method to produce a uniform paste / embolism, which was injected into the defect and allowed to polymerize under tamponade for 3 minutes. There was no leakage at 35 cm of water pressure, and the paste adhered well to the surrounding tissue.

[0159] Evicel fibrin sealant (Example 6). The combination of components was mixed into a paste and directly injected into the defect created using the core device. Local compression was applied to the paste for 3 minutes while the lung was expanded and under positive pressure. No leakage was observed at 20 cm of water pressure. The sealant adhered well to the surrounding tissue. During the same test period, the same formulation was also tested on different lungs, and the formulation also successfully sealed the defect created with a 20 mm biopsy punch.

[0160] Example 11: Ex - vivo Air - Stopping Test

[0161] A needle track seal prototype was evaluated in an ex vivo porcine lung model. The purpose of the test was to evaluate the air-stopping effect of a preformed embolism / paste sealant prototype in closing pleural and parenchymal tissue injuries in the lung after percutaneous or thoracoscopic needle lung biopsy. Fresh lung specimens were collected on the day of the test. Immediately before the test, the lungs were placed on a ventilator to reinflate collapsed alveoli. The lungs were connected to a Respironics ventilator to precisely control the pressure during the ventilation cycle. The pressure was set to an inspiratory pressure of 25 cm of water and an expiratory pressure of 5 cm of water (Δ20 cm of water) to accommodate the lungs.

[0162] During the needle biopsy, the lungs were expanded by setting the ventilator to a constant pressure of 10 cm water (10 cm water inspiratory and expiratory pressures). A needle tract was created in the lung using a 19-gauge biopsy needle, which was inserted through a coaxial needle port positioned 3 cm deep. The prototype embolic agent was inserted into the needle tract using a Biosentry embolization assembly and stylet, or manually inserted by pushing the embolic agent into place using the stylet.

[0163] After the prototype application / insertion, the prototype was allowed to expand and / or polymerize within the lung for a duration of at least 3 minutes while under positive pressure (10 cm water). To test the seal performance, the lungs were ventilated at a 20 cm water pressure differential (25 cm water inspiratory pressure and 5 cm water expiratory pressure, i.e., Δ20 cm water). A bubble test was performed with saline to evaluate the presence and severity of any air leakage. The results obtained for the specific prototypes are shown below.

[0164] Result

[0165] Prototype 1: Lyophilized PEG liquid embolic agent

[0166] Slight leakage was observed at 20 cm water pressure. The leakage was significantly reduced compared to untreated needle tract defects.

[0167] Prototype 2: Lyophilized Evicel fibrin sealant embolic agent

[0168] Slight leakage was observed at 20 cm water pressure. The leakage was significantly reduced compared to untreated needle tract defects.

[0169] Prototype 3: Lyophilized biosynthetic liquid (PEG-SG4 + albumin) embolic agent

[0170] No leakage was observed at 20 cm water pressure.

[0171] Prototype 4: Lyophilized biosynthetic foam embolic agent (2:1 liquid to air ratio)

[0172] When ventilated at 20 cm water pressure, slight leakage was observed at peak pressure. The leakage was significantly reduced compared to untreated needle tract defects.

[0173] Prototype 5: Delivered with an 18-gauge needle / Evicel fibrin sealant paste

[0174] The paste was prepared with 10 mL of Evicel and 2 units After the paste was applied, packing was maintained for 3 minutes to allow coagulation. The preparation was tested at two needle tract defect sites and both successfully achieved air stoppage at 20 cm and 35 cm water pressures.

[0175] Prototype 6: Delivered with an 18-gauge needle + Thrombin (standard paste formulation without fibrinogen).

[0176] After application of the paste, packing was maintained for 3 minutes. The formulation successfully achieved air stoppage at 20 cm water pressure; however, it failed to stop air leakage at 35 cm water pressure.

[0177] Example 12: In - vivo Test

[0178] Testing of the reactive PEG in situ prototype-containing sealant in a live porcine animal model

[0179] 2.5 mL of 228 mg / mL PEG-amine-5k, 50 mM carbonate (pH = 11.0) was combined with one unit of via a dual syringe exchange method by 10 transfers. The mixture was transferred to a 20 mL syringe. 2.5 mL of 300 mg / mL PEG-SG-20k, 50 mM carbonate (pH = 9.0) was combined with 1 unit of via a dual syringe exchange method by 10 transfers. The mixture was transferred to a 20 mL syringe. At the time of application, the two syringes containing / PEG mixture were connected with a dual syringe connector and transferred 8 times. The syringe was connected to the tip and completely extruded within 10 seconds.

[0180] The defect was cored using a coring device. Once the defect was created, the chest cavity was opened. The chest wall distance was measured to be 5 cm in length. The length of the defect in the lung tissue was 4.5 cm. Little bleeding was observed. Preparation of / PEG sealant, and PEG-SG was hydrated for 7 minutes before use. The lung was maintained at approximately 10 cmH 2 O constant pressure. The entire volume of / PEG sealant was pressed into the defect. The sealant flowed easily into the defect and conformed very well to the defect site.

[0181] After 1 minute, no air leakage was observed via a bubble test under full ventilation. The sealant achieved in vivo homeostasis and air stoppage.

Claims

1. A hydrogel - hydrocolloid swellable soft tissue sealant composition, the composition comprising: A cross - linkable electrophilic component; A cross - linkable nucleophilic component; A swellable filler material including gelatin; and A buffer having a pH in the range of about 9.0 to about 10.0; Wherein the composition has a first fluid state and a second cross - linked state, and wherein in the cross - linked state, the electrophilic component and the nucleophilic component cross - link to form a cross - linked hydrogel network; And Wherein the swellable filler material including gelatin is disposed within the cross - linked network.

2. The composition according to claim 1, wherein the gelatin is thermally cross - linked.

3. The composition according to any one of claims 1 or 2, wherein the gelatin is a pre - wetted gelatin fluid.

4. The composition according to any one of claims 1 or 2, wherein the gelatin is dry gelatin particles.

5. The composition according to any one of claims 1 or 2, wherein the swellable filler material includes a blend of pre - wetted gelatin fluid and dry gelatin particles.

6. The composition according to any one of the preceding claims, wherein the swellable filler material is present in the composition in an amount in the range of 50 mg / ml to about 10 mg / ml.

7. The composition according to any one of the preceding claims, wherein in the cross - linked state, the composition has a terminal bubble velocity, and wherein the terminal bubble velocity of the cross - linked composition is at least 75% less than the terminal bubble velocity of a composition comprising the electrophilic component and the nucleophilic component in the absence of the swellable filler.

8. The composition according to claim 7, wherein the terminal bubble velocity of the cross - linked composition is at least 90% less than the terminal bubble velocity of a composition comprising the electrophilic component and the nucleophilic component in the absence of the swellable filler.

9. The composition according to any one of the preceding claims, wherein at least one of the cross - linkable electrophilic component and the cross - linkable nucleophilic component is a synthetic compound.

10. The composition according to claim 9, wherein both the cross - linkable electrophilic component and the cross - linkable nucleophilic component are synthetic compounds.

11. The composition according to claim 10, wherein the electrophilic component comprises a multi - arm polyethylene glycol (PEG) - based polymer, and wherein the nucleophilic component comprises a multi - arm PEG polymer containing at least one reactive amine group.

12. The composition according to any one of claims 9 to 11, wherein the electrophilic component comprises PEG N - hydroxysuccinimide activated ester (PEG - NHS).

13. The composition according to claim 12, wherein the PEG - NHS is PEG - succinimidyl glutarate (PEG - SG).

14. The composition according to any one of claims 1 to 8, wherein at least one of the cross - linkable electrophilic component and the cross - linkable nucleophilic component is a biological compound.

15. The composition according to claim 14, wherein both the crosslinkable electrophilic component and the crosslinkable nucleophilic component are biological compounds.

16. The composition according to claim 15, wherein the electrophilic compound is thrombin and the nucleophilic compound is fibrinogen.

17. The composition according to any one of the preceding claims, wherein the composition is in the crosslinked state and is solid, and further wherein the composition is lyophilized.

18. The composition according to any one of the preceding claims, wherein the swellable filler material is configured to expand in volume in the crosslinked state such that the composition has a crosslinked expandable state, and wherein in the crosslinked expandable state, the composition is configured to provide a fluid-impermeable seal under a water pressure difference of up to 35 cm.

19. A system for forming a hydrogel-hydrocolloid expandable soft tissue sealant, the system comprising: a first container containing a crosslinkable electrophilic component; and a second container containing a crosslinkable nucleophilic component; and a swellable filler material comprising gelatin, wherein the swellable filler material is disposed in the first container, the second container, or both; wherein the first container and the second container are configured to be connected in fluid communication with each other; and wherein the crosslinkable electrophilic component and the crosslinkable nucleophilic component are configured to form a crosslinked hydrogel network when mixed between the first container and the second container, and the swellable material is disposed within the crosslinked hydrogel network.

20. The system according to claim 19, wherein the swellable material is disposed in the first container.

21. The system according to claim 19, wherein the swellable material is disposed in the second container.

22. The system according to claim 19, wherein the swellable material is disposed in each of the first container and the second container.

23. The system according to claim 19, wherein the swellable material is a pre-wetted gelatin fluid.

24. The system according to claim 19, wherein the swellable material is dry gelatin particles.

25. The system according to claim 19, wherein the swellable material comprises both a pre-wetted gelatin fluid and dry gelatin particles.

26. The system according to claim 19, wherein both the first container and the second container contain a pre-wetted gelatin fluid.

27. The system according to claim 19, wherein the first container contains a pre-wetted gelatin fluid and the second container contains dry gelatin particles.

28. The system according to claim 19, wherein the first container contains dry gelatin particles and the second container contains a pre-wetted gelatin fluid.

29. A method of repairing a soft tissue defect, the method comprising: applying a hydrogel-hydrocolloid expandable sealant composition to the soft tissue defect, the composition containing a first crosslinking component, a second crosslinking component, and a swellable filler material comprising gelatin; wherein the soft tissue defect extends from an outer surface of the soft tissue to an inner surface of the soft tissue, and wherein the inner surface defines a fluid-containing void, and the fluid exerts a positive pressure in a direction from the void to the outer surface; The sealant composition is exposed to an aqueous fluid such that the composition will crosslink and swell such that the composition will fluidly seal the defect by adhesion to the soft tissue surface and an expansive force across the soft tissue defect.

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