Freeze-dried cured polymer foam plug

Abstract

The present invention relates to a dried, lyophilized foam plug that is a polymeric reaction product of at least one pair of co-reactive polyethylene glycols, or a blend of a biomaterial and a reactive polyethylene glycol, or a plasma-derived biomaterial reaction product, with substantially all of the reactive moieties being reacted prior to lyophilization, wherein the plug has a microporous structure with an overall pore porosity of about 30-45% and an average pore size generally between 20-95 μm.

Description

Technical Field

[0001] The present invention relates to a freeze-dried hardened polymer hydrogel foam plug particularly suitable for sealing the pulmonary pathway.

Background Art

[0002] Hydrogels, which mean polymer materials that absorb and swell in the presence of an aqueous solution, are known in various forms. The ability to absorb, swell but not dissolve is due to the physical or chemical cross-linking of hydrophilic polymer chains. Hydrogels can be prepared starting from monomers, prepolymers or existing hydrophilic polymers.

[0003] Percutaneous transthoracic needle biopsy techniques are known. Image-guided percutaneous transthoracic needle biopsy (PTNB) is an established technique for patients suspected of pathological conditions such as bronchogenic cancer tumors [1]. The purpose of this technique is to obtain tissue for cytological or histological tests. This technique is typically performed under image guidance by a radiologist. The imaging modalities used include fluoroscopy, computed tomography (CT), and ultrasound. Ultrasound is the safest, quickest, and cheapest method, however, it is only useful for very superficial samples [2]. When the lesion is not suitable for ultrasound, CT is the preferred imaging modality [2].

[0004] PTNB is classified according to the type of needle. Fine needle aspiration biopsy is performed to provide a cytological specimen, and a larger diameter cutting needle produces a histological specimen [2]. Historically, cutting needles have been associated with a relatively high incidence of complications, but with the introduction of automated cutting needles, recent studies have demonstrated similar rates between fine needle aspiration and cutting needles [2].

[0005] During PTNB, an aspiration (18–22 gauge) or cutting needle (14–20 gauge) is placed under image guidance for sample retrieval [1]. A coaxial technique may be used to allow multiple passes through the lung pathway and reduce the number of pleuropunctures [3]. In this technique, a thin-walled guide needle (13–19 gauge) is inserted first and localized to the lesion, after which the aspiration or cutting needle is inserted [1].

[0006] Although this procedure is considered safe and effective, the incidence of pneumothorax remains significant, ranging from 12% to 61%, with 2% to 15% requiring pleural drainage [2, 4]. The risk of pneumothorax is significantly increased if the lesion is not adjacent to the pleura [5]. Most complications occur immediately after biopsy or within the first hour after biopsy. Therefore, after this procedure, the patient is positioned with the puncture site facing down and monitored for at least one hour [1, 2]. The patient may present with shortness of breath, chest pain, and hypoxia [6]. Most acute symptomatic pneumothorax can be detected via chest radiography. Patients with pneumothorax are administered oxygen to expedite its resolution [1].

[0007] Transbronchial needle aspiration (TBNA) is a minimally invasive technique that allows for the collection of mediastinal lymph node samples. When combined with endobronchial ultrasonography (EBUS), precise definition of mediastinal structures is possible.[7] Modern devices incorporate an ultrasound bronchoscope into the needle, enabling real-time visualization of the target area. EBUS-TBNA has been reported to have a high sensitivity of 95.7% in lung cancer screening.[8] As a result, EBUS-TBNA has become widely adopted as the standard treatment for collecting mediastinal lymph node samples.[9]

[0008] EBUS devices consist of a transducer and a processor. The transducer generates and receives sound waves. 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. EBUS-TBNA devices include an ultrasound linear processing array and a retractable needle

[10] . EBUS-TBNA was originally performed with a dedicated 22-gauge aspirator needle, but a larger 21-gauge needle has been introduced very recently

[11] . EBUS-TBNA is limited by the outer diameter of the bronchoscope (6.9 mm) and is therefore performed in the lumen near the bronchi at level 9 [10, 12]. Complications are very low with EBUS-TBNA, but the incidence of pneumothorax remains significant. The pneumothorax rate is estimated to be 0.53% to 16.7% after EBUS-TBNA [9, 12].

[0009] In most institutions worldwide, the choice between TBNA and PTNB still lacks a standardized strategy

[13] . The choice is typically influenced by environmental factors such as the surgeon's experience or institutional resources. There is no established algorithm based on clinical scenarios. However, PTNB is typically preferred for lesions near the visceral pleura, while TBNA is preferred for lesions near the airways.

[0010] Patients with expanding pneumothorax should be treated with the placement of a chest tube [1]. However, there is no universally accepted approach to reduce the rate of pneumothorax

[14] . Several solutions have been employed to reduce the incidence of pneumothorax. Several authors have investigated techniques, including rapid rollover

[14] and deep exhalation and breath-hold techniques

[15] , to reduce the rate of pneumothorax, but these techniques have shown only mild to moderate effects, with a risk reduction of 0.1–15.7%

[15] .

[0011] Therefore, others have investigated the dripping of various encapsulating materials into the pathway, including autologous blood clots

[16] , fibrin glue

[17] , and gelatinous foams[18,19], but none have achieved widespread use in routine practice

[19] . These methods have also suffered from variability, possibly due to surgeon dependence and actual variability

[20] . Autologous blood clots showed moderate efficacy but are plagued by long preparation times in the operating room. Fibrin glue and gelatin techniques have demonstrated some promising published data, but they have not been extensively studied.

[0012] Most recently, synthetic polyethylene glycol plugs have been developed as part of the BioSentry Tract Sealant System (Angiodynamics) [20-22]. In a randomized, multicenter clinical trial, BioSentry resulted in pneumothorax-free 85% of patients, a statistically greater percentage than the control group (69%)

[21] . However, the solid nature of the plugs induces foreign body giant cell reactions and hydrogel encapsulation by 21 days

[23] . [Overview of the Initiative] [Means for solving the problem]

[0013] The present invention relates to a dried lyophilized foam plug, which is a polymer reaction product of at least one pair of co-reactive polyethylene glycols having a reactive moiety, wherein substantially all of the reactive moiety is reacted before lyophilization, and the plug has a microporous structure with an overall pore porosity of about 30–45% and an average pore size of generally 20–95 μm. The average pore size is determined using micro-CT analysis, and the average represents a value in which at least about 80% of the pore volume is within the range.

[0014] The present invention also relates to a dried lyophilized foam plug, which is a polymer reaction product of at least one biomaterial-available electrophilic moiety and at least one reactive polyethylene glycol having a nucleophilic moiety, wherein substantially all of the reactive moiety is reacted before lyophilization, and the plug has a microporous structure with an overall pore void ratio of about 30-45% and an average pore size of generally 20-95 μm.

[0015] The present invention also relates to a dried lyophilized foam fibrin plug, which is a polymer reaction product of a self-reactive derivative of fibrinogen and an activating factor component that generates a self-reactive fibrin (fibrinogen) derivative, wherein substantially all of the fibrinogen is activated before lyophilization to form the fibrin plug, and the fibrin plug has a microporous structure with an overall pore void ratio of about 30-45% and an average pore size of generally 20-95 μm.

[0016] The present invention also relates to a method for sealing lung or bronchial tissue having one or more pathways by inserting or otherwise delivering a foam plug into a defect according to any of the examples described herein. In another embodiment, the method further includes the step of applying a liquid sealant near the plug described herein. In another embodiment, the plug may be applied by passing a coaxial needle after a needle biopsy procedure. In another embodiment, the plug may have a diameter of 10 to 20 mm and is applied using an applicator with a diameter less than or equal to the diameter of the lung pathway resulting from the removal of tumor tissue. In another embodiment, the plug described herein may pass a coaxial needle (0.69 to 1.8 mm) using a stylet.

[0017] The foam plugs described herein may have one or more perforations greater than 100 μm introduced using mechanical means such as a perforator. The foam plugs described herein may have one or more molded or cut perforations greater than 200 μm. In one embodiment, the post-biopsy plug described herein may have a pre-application diameter of about 0.4 to 2 mm. In one embodiment, the post-tumor removal plug described herein may have a pre-application diameter of about 10 to 20 mm. In one embodiment, the plug described herein may further include a contrast agent and / or a therapeutic agent.

[0018] In one embodiment, the plug described herein is a reaction product of synthetic polymer components (4-arm PEG-amine (5k) and 4-arm PEG-SG (20k)). In one embodiment, the plug described herein may be a solid foamed structure stabilized with a surfactant.

[0019] In one embodiment, the present invention is a fibrin plug in which the foamed structure contains a factor XIII sufficient to enhance mechanical integrity and stability.

[0020] In one embodiment, the plug described herein may have one or more ribbed sections, one or more return sections, and / or one or more regions having corrugated topography. The ribbed sections, return sections, or corrugated regions may be molded and / or cut or shaped after freeze-drying. [Modes for carrying out the invention]

[0021] The present invention relates to a pre-formed, polymerized, lyophilized, biosynthetic, synthetic, or biological foam plug or perforated foam plug, preferably cylindrical in shape, that can be applied to a pulmonary pathway after tumor removal and / or biopsy of a tumor nodule via a percutaneous or endobronchial approach. The plug can be used to seal large pulmonary pathways (maximum diameter 20 mm) or needle biopsy pathways (0.41–1.8 mm or 13–22 needle gauge). Larger plugs can be applied using an applicator that is less than or equal to the diameter of the pulmonary pathway. The applicator is inserted into the pulmonary pathway and can be retracted as the plug is inserted. In the case of a percutaneous approach, the needle pathway plug can be inserted via a coaxial needle. The plug can be passed through the coaxial needle using a stylet. In the case of an endobronchial approach, an appropriate endobronchial catheter system can be used. The foam plug can expand immediately upon hydration to form a mechanical seal.

[0022] One embodiment of the device is a foam plug comprising a biosynthesis combination of a proteinaceous component such as albumin and a polyethylene glycol-succinimidyl glutarate (PEG-SG) component, having an air / gas content of about 30-45% by volume, which is fully crosslinked, rapidly frozen at -80°C, and then subjected to freeze-drying. The albumin component may be naturally occurring, such as human serum albumin, or may be produced by recombinant processes. Albumin is provided in the foam-forming mixture at a concentration of about 100-300 mg / ml, preferably about 100 mg / ml. The PEG-SG component may be 2, 3, 4, 6, 8-arm polyethylene glycol succinimidyl glutarate, more preferably 4-arm polyethylene glycol succinimidyl glutarate (PEG-SG4), having a molecular weight of about 1,000-20,000 daltons, added to the foam-forming mixture at a concentration of about 50 mg / ml.

[0023] There are three potential sources of porosity in the lyophilized foam plug: 1) the porosity of the polymer structure (100 - 1000 angstroms), 2) the porosity introduced by the lyophilization process (20 - 40 μm), and 3) the porosity due to foaming (20 - 270 μm). In this particular system, the pores introduced by foaming are thought to create an acceleration of the hydration rate. The resulting plug is elastic, deformable, compressible, and flexible (both radially and axially) before wetting and / or application.

[0024] Being fully crosslinked or fully reacted does not mean that all SG groups have reacted with available nucleophiles. Some SG groups may hydrolyze before or during crosslinking. In addition, some SG and / or nucleophilic groups may be unavailable for reaction due to steric hindrance. Under the selected reaction conditions, defined by the type and amount of electrophiles and nucleophiles and the pH of the reaction, it is intended that all available groups have reacted with their corresponding reactants.

[0025] The step of rapidly freezing the mixture at -80°C for about 1 hour or less is advantageous because the product obtained after the freezing step has a homogeneous distribution of ice crystals that affects the reproducible properties.

[0026] The preferred lyophilization cycle conditions were maintained in a lyophilizer at a condenser temperature of -70°C with the following cycle times.

[0027] [Table 1]

[0028] In a second embodiment of the device, the foam plug consists solely of reaction products of synthetic polymer components such as multi-arm polyethylene glycol PEG-amine and multi-arm PEG-SG to form a PEG-based foam having an air / gas content of approximately 30-45%, the foam structure is stabilized by the addition of a surfactant such as polysorbate-20, the available portion is reacted substantially completely, frozen at -80°C, and freeze-dried to a diameter of approximately 0.69-1.8 mm. The resulting plug is tough, elastic, deformable, and flexible.

[0029] The PEG-amine component consists of a poly(ethylene glycol)amine macromer such as a linear bifunctional poly(ethylene glycol)amine or an n-arm poly(ethylene glycol)amine (wherein n is an integer of 2 or more). In this embodiment, the preferred PEG-amine has four arms and a molecular weight of at least 5000 daltons (5k).

[0030] The PEG-SG component consists of a poly(ethylene glycol)SG macromer such as a linear bifunctional poly(ethylene glycol)SG or n-arm poly(ethylene glycol)SG (wherein n is an integer of 2 or more). In this embodiment, the preferred PEG-SG has four arms and a molecular weight of at least 5000 daltons (5k).

[0031] A third embodiment of the device may be a plasma-derived biological foam. Such a plasma-derived biological foam can be prepared by combining a fibrinogen component with an activator such as thrombin at a low activity level (2-50 IU / mL) to avoid rapid polymerization, and introducing air / gas at a desired level of approximately 30-45% air / gas content. Once the available fibrin has polymerized, the resulting biological foam is frozen at -80°C and freeze-dried.

[0032] Each of the foam plugs described above is packaged, sterilized, and applied for use in a dry state, meaning that the plug does not contain any significant moisture other than that resulting from the surrounding environment. More preferably, the plug is considered dry with a moisture content of less than 8%, more preferably less than about 5%, and most preferably less than 3% under normal room conditions.

[0033] Each of the foam plugs described above is a reaction product of a biomaterial having plasma-derived components, a synthetic reactive polymer, and / or polymerizable reactive groups. For the purposes of this application, the reaction product refers to a material that has been subjected to appropriate time and conditions for reacting all or substantially all of the available reactive groups with a co-reactive moiety and / or a chemical crosslinking agent, preferably having at least two reactive groups.

[0034] The foam plug described above may be applied in combination with biosynthetic, synthetic, or biological liquid sealants to achieve pneumostasis and hemostasis control. Liquid sealants used in combination with the plug may include a liquid solution of a nucleophile (e.g., albumin or PEG-amine) and PEG-SG, which are pre-mixed immediately before use, or a biological liquid sealant (i.e., a fibrin sealant formulation containing a fibrinogen component and a fibrinogen activator or polymerization agent). These liquid sealants may be applied before, during, or after insertion of the foam plug. The liquid sealant needs to be crosslinked for a sufficient time, 5 seconds to 5 minutes, to form a seal inside and on the surface of the lung to prevent air leakage.

[0035] A particularly preferred foam can be formed by reacting 25-100 mg / mL of multi-arm PEG having more than three (3) electrophiles with a molecular weight of 5 kDa-20 kDa with approximately 50-200 mg / mL of albumin, and may have an air content of approximately 30-45%. A particularly preferred reaction formulation contains 75 mg / mL of 4-arm PEG-SG(20k) and 10% albumin (meaning 100 mg / mL), where generally, the percentage refers to the number of grams of the substance in 100 mL of water and 50 mM carbonate buffer (pH=9.0).

[0036] A preferred foam plug exhibits a faster hydration time as a result of the foam's porous structure, which allows for faster water penetration of the plug, leading to faster swelling of the plug for increased mechanical sealing. The volume increase can be controlled based on the original foam (container) dimensions.

[0037] Preferred foam plugs also exhibit a fast absorption time because the foam consists of a large percentage of air (or gas), reducing the mass of the implanted material and allowing for faster absorption during healing. The absorption time of PEG foams can be further adjusted based on the biodegradability of the PEG crosslinking agent. The absorption time of plasma biological foams can be adjusted by changing the amounts of fibrinogen and factor XIII in the biological foam.

[0038] A preferred foam plug is a flexible, compressible foam that allows for insertion into the lung pathway and subsequent expansion for immediate mechanical sealing. The shape of the foam may be cylindrical or tapered to generate differential pressure on the tissue within the pathway.

[0039] A preferred foam plug is one that, once hydrated, is sufficiently flexible so that the foam can expand and contract with the natural movements of the breathing lungs.

[0040] A preferred foam plug has a high volume-to-mass ratio because the foam is mostly composed of air (or gas), with the liquid phase accounting for only 55-70% of the volume, meaning that 30-45% of the foam plug's volume is gas.

[0041] Preferred foam plugs may optionally contain contrast agents used during X-ray imaging, such as iohexol, also known as Omnipaque and Hexopaque. The latter contrast agent has been shown not to affect the quality of the PEG-albumin foam.

[0042] The present invention describes a preferably cylindrical, lyophilized, biosynthetic, synthetic, or biological foam plug applied to the pulmonary pathway after percutaneous or endobronchial biopsy procedures to prevent pneumothorax. The percutaneous approach may include either a needle biopsy procedure (0.41–1.8 mm in diameter) or a coring procedure (<20 mm in diameter) to remove a tumor nodule. The foam plug may expand immediately upon hydration to form a mechanical seal. The foam plug may be applied in combination with a biosynthetic, synthetic, or biological liquid sealant to achieve emphysema and hemostatic control.

[0043] One embodiment of the device is a foam plug or perforated foam plug consisting of a biosynthesis combination of a protein component (e.g., albumin) and polyethylene glycol succinimidyl glutarate (PEG-SG) (30-45% air / gas content), which is fully crosslinked, frozen at -80°C, and freeze-dried to a diameter of 0.41-1.8 mm. The resulting plug is tough, elastic, deformable, and flexible. The plug can be passed through a coaxial needle after a needle biopsy procedure.

[0044] In another embodiment of the device, the biosynthetic plug may have a diameter of 10–20 mm and can be applied using a small applicator (<20 mm) smaller than the diameter of the lung pathway resulting from the removal of tumor tissue. The applicator is inserted into the lung pathway and can be retracted as the plug is inserted.

[0045] In another embodiment of the device, the biodegradable material may be combined with a non-ionic contrast agent (e.g., iohexol) for radiopaqueness. The contrast agent may allow for site localization at a later date.

[0046] In another embodiment of the device, the biodegradable material may be combined with a contrast agent to facilitate detection by magnetic resonance imaging. The contrast agent may enable localization of the site at a later date.

[0047] In another embodiment of the device, the biodegradable material may be combined with a radioactive agent for a radiation detection method. The radioactive agent may enable localization of the site at a later date.

[0048] In another embodiment of the device, the biodegradable material may be combined with a therapeutic agent. The therapeutic agent (e.g., a chemotherapeutic agent) may provide local drug delivery for cancer management.

[0049] In a second embodiment of the device, the foam is a reaction product of synthetic polymer components only (e.g., 4-arm PEG-amine (5k) and 4-arm PEG-SG (20k)), forming a PEG-based foam with an air / gas content of about 30-45 vol% and a foam structure stabilized with a surfactant (e.g., polysorbate-20) to which substantially all available reactive parts have reacted, which is frozen at -80°C and freeze-dried to a diameter of 0.41-1.8 mm. The resulting plug is tough, elastic, deformable, and flexible. The plug can be passed through a coaxial needle (0.69-1.8 mm) using a stylet.

[0050] In another embodiment of the device, the synthetic plug may have a diameter of 10–20 mm and can be applied using an applicator less than or equal to the diameter of the lung pathway resulting from the removal of tumor tissue (<20 mm). The applicator is inserted into the lung pathway and can be retracted as the plug is inserted.

[0051] In a third embodiment of the device, the foam may consist of fibrin obtained by foaming a mixture of low-activity fibrinogen with a fibrinogen activator such as thrombin or a polymerizing agent, by introducing air or gas. The perforated fibrin is polymerized, frozen at -80°C, and freeze-dried to a diameter of 0.41–1.8 mm. The resulting plug is tough, elastic, deformable, and flexible. The plug can be passed through a coaxial needle (0.69–1.8 mm) using a stylet.

[0052] In another embodiment of the device, the biological plug may have a diameter of less than 20 mm and can be applied using a small applicator (approximately 20 mm) smaller than the diameter of the lung pathway resulting from the removal of tumor tissue. The applicator is inserted into the lung pathway and can be retracted as the plug is inserted.

[0053] In another embodiment of the device, the fibrin foam may be crosslinked using factor XIII to enhance the mechanical integrity and stability of the foam. In another embodiment of the device, the plug may be fabricated to include ribbed features to improve the plug's ability to resist extrusion under pressure.

[0054] In another embodiment of the device, the plug may have an oversized dimension to improve its ability to resist extrusion under pressure.

[0055] In another embodiment of the device, the plug may have further pores to improve the hydration and reabsorption of the plug, which is manufactured via perforations, molds with removable pins, and the like.

[0056] In another embodiment of the device, the plug is inserted using a stylet. In another embodiment of the device, the plug is inserted to the desired position using pneumatic pressure. In another embodiment of the device, the plug is held in a cylindrical mesh, moved to position, and the plug is unfolded by expanding the mesh. [Examples]

[0057] Example 1: Biosynthesis, synthesis, and biological plug formulations 1. Biosynthesis solution: 75 mg / mL of 4-arm PEG-SG-20k, 10% albumin, 50 mM carbonate (pH=9.0) 2. Biosynthetic high-density foam: 75 mg / mL of 4-arm PEG-SG-20k, 10% albumin, 50 mM carbonate (pH=9.0) (2:1 liquid-to-air ratio, 66% air) 3. Biosynthetic low-density foam: 75 mg / mL of 4-arm PEG-SG-20k, 10% albumin, 50 mM carbonate (pH=9.0) (1:2 liquid-to-air ratio, 33% air) 4. Synthetic solution: 75 mg / mL 4-arm PEG-SG-20k, 57 mg / mL 4-arm PEG-NH2-5k, 50 mM carbonate (pH=9.0) 5. Fibrin encapsulant

[0058] These formulations were hydrated in phosphate-buffered saline. The increase in mass due to hydration was measured at 5 and 10 minutes. The synthetic formulation hydrated five times more than the biosynthetic and fibrin encapsulant formulations. There was no significant difference in hydration between the biosynthetic and fibrin encapsulant formulations. Approximately 82% hydration occurred by 5 minutes, but there was a significant difference in hydration between 5 and 10 minutes. Although the synthetic formulation showed significantly greater hydration than the other formulations, it exhibited poor cohesive properties. This is demonstrated by significantly lower tensile stiffness and ultimate tensile stress. This reduction in cohesive properties results in poor sealing performance in the needle pathway.

[0059] Example 2: Biosynthetic formulations of 75 mg / mL 4-arm PEG-SG-20k, 10% albumin, and 50 mM carbonate (pH=9.0) were tested. For each group tested, 750 mg of PEG-SG4-20k was dissolved in 5 mL of 100 mM carbonate buffer (pH=9.0). PEG-SG4-20k was filled into a 20 mL slip-tip syringe, and the plunger was positioned to the corresponding mark in the table below. 5 mL of 20% albumin was filled into a 20 mL syringe, and the plunger was positioned to the corresponding mark in the table below. The syringes were connected using a dual syringe connector, and the solutions were passed through 20 times. The syringes were immediately connected to a needle, and the foam was slowly squeezed out until a few drops were evaluated. The needle tip was then pierced through a rubber stopper, and the needle was removed from the syringe. Once fully crosslinked, the needle was removed from the rubber stopper.

[0060] [Table 2]

[0061] The foaming of the formulation increased the hydration rate of the biosynthetic formulation. The effect of foaming was evaluated in biosynthetic formulations with 0% (solid), 33%, and 66% air content. Foaming plugs (33% and 66% air) hydrated approximately 2.5 times more than solid plugs. There was no significant difference between the 33% and 66% air plugs, but foaming plugs hydrated significantly more than solid plugs.

[0062] Air content of 0%, 15%, 30%, 45%, and 60% was tested. The air content in the freeze-dried foam had a significant effect on hydration in 5 minutes (p<0.01, one-way ANOVA). Specifically, the 45% air content showed significantly greater hydration than the foams with 0% and 15% air. In addition, tests for equal variances showed that the variances differed significantly across all groups (p<0.01). Therefore, a series of tests for the two variances showed that the variance of the 60% air foam was significantly greater than that of the 30% and 45% air foams, demonstrating that the hydration rates of the 60% air foam were inconsistent.

[0063] The air content in the freeze-dried foam had a significant effect on hydration at 10 minutes (p<0.01, one-way ANOVA). Specifically, foams with an air content of 30% or more showed significantly greater hydration than foams with 0% and 15% air content. The dispersion of 30%, 45%, and 60% air content foams did not differ significantly at 10 minutes. Therefore, pre-formed freeze-dried foam plugs with an air content of 30% to 45% yield the best hydration with the least dispersion at 5 minutes. Foams with an air content of 30% to 60% yield the best hydration at 10 minutes.

[0064] Example 3: Ex vivo results The foam plug prototypes were evaluated for their ability to achieve emphysema in an Exvivovuda lung model. In this model, lung resection tissue was freshly collected on the day of the test and kept moist until the test. Before the test, the lung was placed on a ventilator and the collapsed alveoli were mobilized (the goal was to open the collapsed atelectasis alveoli). During the test, the lung was connected to a Respironics ventilator, and the pressure during ventilation and circulation was precisely controlled. The pressure was set to an inspiratory pressure of 25 cm³ and an expiratory pressure of 5 cm³ (a difference of 20 cm³).

[0065] A lung puncture wound was created in the lung using a 12mm puncture device (Acu-punch), and this wound was connected to a ventilator and circulation. The wound size was measured after puncture and was approximately 1.5 cm in diameter and 3 cm in depth in the inflated lung. Air leakage in the wound was evaluated as severe in the bubble test. When the prototype was applied, the pressure was reduced to an inspiratory pressure of 10 cm³ of water column and an expiratory pressure of 10 cm³ of water column (unchanged) in order to keep the lung inflated.

[0066] After the prototype was applied, local compression was typically applied to the prototype for 1 minute while the lung was still expanded and under positive pressure. To test performance, the lung was ventilated starting at low pressure and increasing to an inspiratory pressure of 25 cmH / s and an expiratory pressure of 5 cmH / s (20 cmH / s difference). The air bubble test was performed by passing saline solution through the puncture site and recording the presence and severity of air leaks. For an additional challenge, the ventilation pressure was increased to an inspiratory pressure of 40 cmH / s and an expiratory pressure of 5 cmH / s (35 cmH / s difference). After the pressure test, the prototype was withdrawn from the puncture site and adhesion to the surrounding tissue was qualitatively evaluated. The specific prototype tested is indicated in the caption of each image. Both foam plug prototypes sealed air leaks at both 20 and 35 cmH / s when used in combination with fibrin encapsulants, Evicel, or PEG-albumin liquid encapsulants.

[0067] Example 4: The needle tract sealing prototype was evaluated in an Exvivovuda lung model. The objective of the study was to evaluate the effectiveness of pre-formed plug / paste sealing prototypes in preventing lung leaks for closure of pleural and parenchymal lesions in the lung after percutaneous or thoracoscopic needle lung biopsy. A fresh lung resection was collected on the day of the study. Immediately before the study, the lung was placed on a ventilator and collapsed alveoli were mobilized. The lung was connected to a Respironics ventilator, and the pressure during ventilation and circulation was precisely controlled. To allow the lung to adapt, the pressure was set to an inspiratory pressure of 25 cm³ and an expiratory pressure of 5 cm³ (a difference of 20 cm³).

[0068] During needle biopsy, the lungs were expanded by setting the ventilator to a constant pressure of 10 cm³ of water (10 cm³ of inspiratory and expiratory pressure). The needle pathway was created in the lung using a 19-gauge biopsy needle inserted through a coaxial needle port positioned at a depth of 3 cm. The prototype plug was inserted into the needle pathway using a commercially available plug assembly and stylet, or manually inserted by pushing the plug into position using a stylet.

[0069] After application / insertion of the prototype, it was possible for the prototype to expand and / or polymerize in the lung under positive pressure (10 cm hydride) for at least 3 minutes. To test the sealing performance, the lung was ventilated with a pressure difference of 20 cm hydride (inspiratory pressure of 25 cm hydride and expiratory pressure of 5 cm hydride, i.e., a difference of 20 cm hydride). A bubble test with physiological saline was performed to evaluate the presence and severity of air leaks. The results obtained for specific prototypes are shown below.

[0070] result: Prototype: Freeze-dried Surgifoam / Surgiflo PEG liquid plug (L1-6). Slight leakage was observed at a pressure of 20 cm of water column. Leakage was significantly reduced compared to untreated needle pathway defects.

[0071] Prototype: Freeze-dried Evicel fibrin encapsulant plug (L1-7). Slight leakage was observed at a pressure of 20 cm of water column. Leakage was significantly reduced compared to untreated needle pathway defects.

[0072] Prototype: Freeze-dried biosynthetic liquid (PEG-SG4 + albumin) plug (L2-1). No leakage was observed at a pressure of 20 cm of water column.

[0073] Prototype: Freeze-dried biosynthetic foam plug (2:1 liquid to air) (L2-5). When ventilated at a pressure of 20 cm of water column, slight leakage was observed at the peak pressure. Leakage was significantly reduced compared to the untreated needle pathway defect.

[0074] PCT PCT1. A dried lyophilized foam plug which is a polymer reaction product of at least one pair of co-reactive polyethylene glycols having a reactive moiety, wherein substantially all of the reactive moiety is reacted before lyophilization, and the plug has a microporous structure with an overall pore void ratio of about 30-45% and an average pore size of generally 20-95 μm.

[0075] PCT2. A dried lyophilized foam plug, which is a polymer reaction product of at least one biomaterial-available electrophilic moiety and at least one reactive polyethylene glycol having a nucleophilic moiety, wherein substantially all of the reactive moiety is reacted before lyophilization, and the plug has a microporous structure with an overall pore void ratio of about 30-45% and an average pore size of generally 20-95 μm.

[0076] PCT3. A dried, freeze-dried foam fibrin plug, which is a polymer reaction product of a self-reactive derivative of fibrinogen and an activating factor component that generates a self-reactive fibrin (fibrinogen) derivative, wherein substantially all of the reactive groups of the fibrinogen derivative react before freeze-drying to form the fibrin plug, and the fibrin plug has a microporous structure with an overall pore void ratio of approximately 30-45% and an average pore size of generally 20-95 μm.

[0077] PCT4. A method for sealing lung or bronchial tissue having one or more pathways, comprising inserting a foam plug as described in any of the preceding paragraphs into a defect.

[0078] A plug according to any one of PCT1 to 3, having one or more perforations larger than PCT5.40 μm.

[0079] A plug according to any one of PCT1 to 3, having one or more molded or cut perforations larger than PCT6.40 μm.

[0080] PCT7. A post-biopsy plug described in any one of PCT1-3, having a pre-application diameter of approximately 0.4-2 mm.

[0081] PCT8. A post-tumor removal plug described in any one of PCT1-3, having a pre-application diameter of approximately 10-20 mm.

[0082] PCT9. A plug as described in any one of PCT1-3, further containing a contrast agent.

[0083] PCT10. A plug described in any one of PCT1-3, further containing the therapeutic agent.

[0084] PCT11. A plug according to any one of PCT1 to 3, which is a reaction product of synthetic polymer components (4-arm PEG-amine and 4-arm PEG-SG).

[0085] PCT12. A plug according to any one of PCT1 to 3, wherein the solid foam structure further comprises a surfactant.

[0086] PCT13. A fibrin plug according to any one of PCT1-3, wherein the foamed structure contains sufficient factor XIII to enhance mechanical integrity and stability.

[0087] PCT14. A plug according to any one of PCT1 to 3, having one or more ribbed sections, one or more return sections, and / or one or more regions having waveform topography.

[0088] PCT15. A plug according to any one of PCT1 to 3, wherein the ribbed section, return section, or corrugated region is molded and / or cut or shaped after freeze-drying.

[0089] A method further comprising applying a liquid sealant near the plug described in PCT16.PCT1-3.

[0090] A method in which a plug described in any one of PCT1-3 is applied by passing a coaxial needle through it after a needle biopsy procedure.

[0091] A method in which a plug described in any one of PCT1-3 has a diameter of 10-20 mm and is applied using an applicator smaller than the diameter of the lung tract resulting from the removal of tumor tissue.

[0092] A method in which a plug described in any one of PCT1-3 passes through a coaxial needle (0.69-1.8mm) using a stylet.

[0093] [Implementation Method] (1) A dried lyophilized foam plug which is a polymer reaction product of at least one pair of co-reactive polyethylene glycols having a reactive portion, wherein substantially all of the reactive portion is reacted before lyophilization, and the plug has a microporous structure with an overall pore void ratio of about 30-45% and an average pore size of generally 20-95 μm. (2) A dried lyophilized foam plug which is a polymer reaction product of at least one biomaterial-usable electrophilic moiety and at least one reactive polyethylene glycol having a nucleophilic moiety, wherein substantially all of the reactive moiety is reacted before lyophilization, and the plug has a microporous structure with an overall pore void ratio of about 30-45% and an average pore size of generally 20-95 μm. (3) A dried lyophilized foam fibrin plug, which is a polymer reaction product of a self-reactive derivative of fibrinogen and an activating factor component that generates a self-reactive fibrin (fibrinogen) derivative, wherein substantially all of the reactive groups of the fibrinogen derivative react to form a fibrin plug before lyophilization, and the fibrin plug has a microporous structure with an overall pore void ratio of about 30-45% and an average pore size of generally 20-95 μm. (4) A method for sealing lung or bronchial tissue having one or more pathways, comprising inserting a foam plug as described in Embodiment 2 into a defect. (5) The plug according to Embodiment 2, having one or more perforations larger than 40 μm.

[0094] (6) The plug according to Embodiment 2, having one or more molded or cut perforations larger than 40 μm. (7) A post-biopsy plug according to Embodiment 2, having a pre-application diameter of approximately 0.4 to 2 mm. (8) A post-tumor removal plug according to Embodiment 2, having a pre-application diameter of approximately 10-20 mm. (9) The plug according to Embodiment 2, further comprising a contrast agent. (10) The plug according to Embodiment 2, further comprising a therapeutic agent.

[0095] (11) The plug according to Embodiment 1, which is the reaction product of the synthetic polymer components (4-arm PEG-amine and 4-arm PEG-SG). (12) The plug according to Embodiment 3, wherein the solid foam structure further comprises a surfactant. (13) The fibrin plug according to Embodiment 3, wherein the foamed structure contains a factor XIII sufficient to enhance mechanical integrity and stability. (14) The plug according to Embodiment 2, having one or more ribbed sections, one or more return sections, and / or one or more regions having a waveform topography. (15) The plug according to Embodiment 2, wherein the ribbed section, return portion, or corrugated region is molded and / or cut or shaped after freeze-drying.

[0096] (16) A method further comprising applying a liquid sealant near the plug described in Embodiment 2. (17) A method wherein the plug described in Embodiment 2 is applied by passing a coaxial needle through it after a needle biopsy procedure. (18) A method wherein the plug described in Embodiment 2 is applied using an applicator having a diameter of 10 to 20 mm and less than or equal to the diameter of the lung tract resulting from the removal of tumor tissue. (19) A method wherein the plug described in Embodiment 2 passes through a coaxial needle (0.69-1.8 mm) using a stylet.

Claims

1. A dried, freeze-dried foam plug which is a polymer reaction product of at least one polyethylene glycol succinimidyl glutarate and at least one albumin, wherein substantially all of the reaction product is reacted before freeze-drying, and the plug has a microporous structure with an overall pore void ratio of 30-45% and an average pore size of approximately 20-95 μm.

2. The plug according to claim 1, wherein the at least one polyethylene glycol succinimidyl glutarate comprises a 2, 3, 4, 6, or 8-arm polyethylene glycol succinimidyl glutarate.

3. The plug according to claim 1, wherein the at least one polyethylene glycol succinimidyl glutarate comprises four-arm polyethylene glycol succinimidyl glutarate.

4. The plug according to claim 1, wherein the at least one polyethylene glycol succinimidyl glutarate is 4-arm polyethylene glycol succinimidyl glutarate.

5. The plug according to claim 1, wherein the at least one polyethylene glycol succinimidyl glutarate comprises 4-arm PEG-SG-20k.

6. The plug according to claim 1, wherein the at least one polyethylene glycol succinimidyl glutarate is 4-arm PEG-SG-20k.

7. A plug according to claim 1 for use in a method of sealing lung or bronchial tissue having one or more pathways, wherein the method comprises inserting the plug into a defect.

8. The plug according to claim 1, having one or more perforations larger than 40 μm.

9. The plug according to claim 1, having one or more molded or cut perforations larger than 40 μm.

10. A plug according to claim 1 for use in biopsy, having a pre-application diameter of 0.4 to 2 mm.

11. A plug according to claim 1 for use in tumor removal, having a pre-application diameter of 10 to 20 mm.

12. The plug according to claim 1, further comprising a contrast agent.

13. The plug according to claim 1, further comprising a therapeutic agent.

14. The plug according to claim 1, having one or more ribbed sections, one or more return sections, and / or one or more regions having waveform topography.

15. The plug according to claim 1, wherein the ribbed section, return portion, or corrugated region is molded and / or cut or shaped after freeze-drying.

16. A plug according to claim 7, wherein the method further comprises applying a liquid sealant near the plug.

17. A plug according to claim 7, wherein the method is applied by passing the plug through a coaxial needle after a needle biopsy procedure.

18. A plug according to claim 7, wherein the plug has a diameter of 10 to 20 mm, and the method further comprises applying the plug using an applicator with a diameter less than or equal to the diameter of the lung pathway resulting from the removal of tumor tissue.

19. A plug according to claim 7, wherein the method further comprises the plug passing a coaxial needle (0.69 to 1.8 mm) using a stylet.

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