Biocompatible adhesive material and method of use thereof

Abstract

A biocompatible adhesive material is provided for use with living tissue and / or medical implants and the like, as well as methods and kits for making and using the biocompatible adhesive material. The biocompatible adhesive material includes a functionalized poloxamer component and an oxidized polysaccharide component, and can be tailored for specific tissue types and conditions.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 336,528, filed April 29, 2022. [Background technology]

[0002] Many tissue adhesives are used in a variety of medical procedures and applications, including topical wound closure, supplementing or replacing surgical sutures or staples, adhering synthetic materials to living tissue, and drug delivery. However, many known tissue adhesives are not suitable for many applications due to, for example, toxic degradation products, slow curing, poor mechanical strength, and other drawbacks.

[0003] Several types of hydrogel adhesives have been developed that are non-toxic and have improved properties. These hydrogels are generally formed by reacting a component that has nucleophilic groups with a component that has electrophilic groups that react to form a crosslinked network. However, these hydrogels typically dissolve too quickly, do not have sufficient adhesive power, or do not have sufficient mechanical strength. Summary of the Invention [Problem to be solved by the invention]

[0004] It would therefore be desirable to provide an improved adhesive formulation that overcomes one or more of the above-mentioned disadvantages. [Means for solving the problem]

[0005] Kind Code: A1 Biocompatible adhesive materials designed for sealing, coating, bonding, or protecting biological and prosthetic materials are disclosed.

[0006] In one embodiment: A block copolymer comprising one or more polyethylene oxide (PEO) blocks, one or more polypropylene oxide (PPO) blocks, and at least one primary amine group; and Oxidized polysaccharides containing at least two aldehyde moieties A biocompatible adhesive material is disclosed, comprising: The adhesive material is crosslinked by a plurality of imine moieties formed from at least one primary amine of the block copolymer and at least two aldehyde moieties of the oxidized polysaccharide; the adhesive material is a hydrogel.

[0007] In one embodiment: a functionalized poloxamer represented by FG-PEO-PPO-PEO-FG, where each FG independently represents H or a linker-amine moiety, and where at least one of the FGs is not H, and each linker-amine moiety independently comprises at least one primary amine; and Oxidized polysaccharides containing at least two aldehyde moieties A biocompatible adhesive material is disclosed, comprising: The adhesive material is crosslinked by a plurality of imine moieties formed from at least one primary amine of the linker-amine portion of the functionalized poloxamer and an aldehyde moiety of the oxidized polysaccharide; the adhesive material is a hydrogel.

[0008] In one embodiment, a method for treating, adhering, or sealing one or more biological tissues or artificial materials is disclosed, the method comprising: Providing a block copolymer comprising one or more polyethylene oxide (PEO) blocks, one or more polypropylene oxide (PPO) blocks, and at least one primary amine group; providing a second component comprising an oxidized polysaccharide comprising at least two aldehyde moieties; Producing an adhesive formulation by combining the first component and the second component; contacting the adhesive formulation with one or more biological tissue surfaces; and Allowing the adhesive formulation to harden in adhesion to one or more biological tissue surfaces. Includes.

[0009] In one embodiment, a method for treating, adhering, or sealing one or more biological tissues or artificial materials is disclosed, the method comprising: providing a first component comprising a functionalized poloxamer represented by FG-PEO-PPO-PEO-FG, where each FG independently represents H or a linker-amine moiety, and where at least one of the FGs is not H and each linker-amine moiety independently comprises at least one primary amine; providing a second component comprising an oxidized polysaccharide comprising at least two aldehyde moieties; Producing an adhesive formulation by combining the first component and the second component; contacting the adhesive formulation with one or more biological tissue surfaces; and Allowing the adhesive formulation to harden in adhesion to one or more biological tissue surfaces. Includes.

[0010] In one embodiment: a first component comprising a block copolymer comprising one or more polyethylene oxide (PEO) blocks, one or more polypropylene oxide (PPO) blocks, and at least one primary amine group; and a second component comprising an oxidized polysaccharide comprising at least two aldehyde moieties; a first syringe; and User manual A kit is disclosed comprising:

[0011] In one embodiment: a first component comprising a functionalized poloxamer represented by FG-PEO-PPO-PEO-FG, where each FG independently represents H or a linker-amine moiety, and where at least one of the FGs is not H and each linker-amine moiety independently comprises at least one primary amine; and a second component comprising an oxidized polysaccharide comprising at least two aldehyde moieties; a first syringe; and User manual A kit is disclosed comprising:

[0012] In one embodiment: A biocompatible adhesive material as disclosed herein; and An effective amount of at least one drug A drug delivery composition is disclosed, comprising: At least one drug is mixed with the biocompatible adhesive material.

[0013] The novel features of the invention are set forth with particularity in the appended claims. A more detailed understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description, which sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also referred to herein as "figures" or "FIG.") in which: [Brief description of the drawings]

[0014] [Figure 1] 1 is a scheme showing a strategy for constructing a family of modified poloxamers. [Diagram 2] The gelation mechanism of the hydrogel is shown. Amine-modified poloxamer can achieve thermal gelation, and the addition of oxidized dextran can achieve rapid gelation independent of temperature. [Diagram 3] 1 shows a scheme of covalent interactions. [Figure 4] 1 shows a scheme of ionic interactions. [Diagram 5] 1 shows a scheme of mechanical interlocking. [Figure 6] FIG. 1 shows a surface response model of gelation time with various concentrations of oxidized dextran and PEI-modified poloxamer-188 (PluPEI). [Figure 7] 1 shows a surface response model of hydrogel swelling upon combination of various concentrations of PEI-modified poloxamer 188 (PluPEI) and oxidized dextran. [Figure 8A] It demonstrates that a thin layer of material can be bent through 180° without the material cracking or breaking. [Figure 8B] It demonstrates that a thick layer of material can be bent through 180° without the material cracking or breaking. [Figure 9] 1 shows the fracture pressure of several dextran (Dex)-PluPEI hydrogels at t0 (0 h) and t24 (24 h). [Figure 10] 1 shows the buffering capacity of various hydrogel formulations. [Figure 11] Swelling of specific formulations at 24 hours is shown. [Figure 12] 1 shows the in vitro drug release profile of acriflavine for several hydrogel formulations. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Improved biocompatible adhesive materials, compositions and methods have been developed for adhering, sealing or treating one or more biological tissues. In general, these biocompatible adhesive materials include a functionalized poloxamer component and an oxidized polysaccharide component. In some embodiments, the adhesive formulations are used as tissue adhesives, tissue sealants, tissue treatments, matrix materials, fillers, coatings, or combinations thereof.

[0016] In one embodiment: A block copolymer comprising one or more polyethylene oxide (PEO) blocks, one or more polypropylene oxide (PPO) blocks, and at least one primary amine group; and Oxidized polysaccharides containing at least two aldehyde moieties A biocompatible adhesive material is disclosed, comprising: The adhesive material is crosslinked by a plurality of imine moieties formed from at least one primary amine of the block copolymer and at least two aldehyde moieties of the oxidized polysaccharide; the adhesive material is a hydrogel.

[0017] In certain embodiments, the molecular weight of the block copolymer is from about 1,000 Da to about 25,000 Da, or from about 1,000 Da to about 20,000 Da.

[0018] In certain embodiments, the block copolymer is inverse thermosensitive.

[0019] In certain embodiments, the block copolymer comprises from 1 to about 50 primary amines. In certain embodiments, the block copolymer comprises from 1 to about 25 primary amines.

[0020] In certain embodiments, the block copolymer has a PEO block:PPO block ratio of about 50:50 to about 80:20. The PEO block:PPO block ratio is the ratio of the number of PEO units to the number of PPO units.

[0021] In certain embodiments, the block copolymer is FG-(poloxamer 188)-FG, FG-(poloxamer 237)-FG, FG-(poloxamer 338)-FG, FG-(poloxamer 407)-FG, or any combination thereof, where each FG independently represents H or a primary amine group, and at least one of the FGs is not H.

[0022] In certain embodiments, the primary amine groups are each independently 1,2-diaminoethane, tris(2-aminoethyl)amine, or low molecular weight (e.g., less than about 2,000 daltons, less than 1,000 daltons, less than 500 daltons, or less than 250 daltons) polyethyleneimine. For example, the primary amine groups are 1,2-diaminoethane residues, tris(2-aminoethyl)amine residues, or combinations thereof. In certain embodiments, the primary amine groups are provided by modification of a poloxamer with 1,2-diaminoethane, tris(2-aminoethyl)amine, or combinations thereof.

[0023] In one embodiment: a functionalized poloxamer represented by FG-PEO-PPO-PEO-FG, where each FG independently represents H or a linker-amine moiety, and where at least one of the FGs is not H, and each linker-amine moiety independently comprises at least one primary amine; and Oxidized polysaccharides containing at least two aldehyde moieties A biocompatible adhesive material is disclosed, comprising: The adhesive material is crosslinked by a plurality of imine moieties formed from at least one primary amine of the linker-amine portion of the functionalized poloxamer and an aldehyde moiety of the oxidized polysaccharide; the adhesive material is a hydrogel.

[0024] In certain embodiments, both FGs represent a linker-amine moiety.

[0025] In certain embodiments, the molecular weight of the functionalized poloxamer is from about 1,000 Da to about 25,000 Da, or from about 1,000 Da to about 20,000 Da.

[0026] In certain embodiments, the functionalized poloxamer is inverse thermolabile.

[0027] In certain embodiments, each linker-amine moiety contains from 1 to about 50 primary amines.

[0028] In certain embodiments, each linker-amine moiety contains from 1 to about 25 primary amines.

[0029] In certain embodiments, the functionalized poloxamer has a PEO:PPO ratio of about 50:50 to about 80:20. The PEO:PPO ratio is the ratio of the number of PEO units to the number of PPO units.

[0030] In certain embodiments, the functionalized poloxamer is FG-(poloxamer 188)-FG, FG-(poloxamer 237)-FG, FG-(poloxamer 338)-FG, FG-(poloxamer 407)-FG, or any combination thereof.

[0031] In certain embodiments, the amine moieties of the linker-amine moiety are each independently 1,2-diaminoethane, tris(2-aminoethyl)amine, or a low molecular weight (e.g., less than about 2,000 daltons, less than 1,000 daltons, less than 500 daltons, or less than 250 daltons) polyethyleneimine. For example, the amine moieties of the linker-amine moiety are 1,2-diaminoethane residues, tris(2-aminoethyl)amine residues, or combinations thereof. In certain embodiments, the amine moieties of the linker-amine moiety are provided by modification of a poloxamer with 1,2-diaminoethane, tris(2-aminoethyl)amine, or combinations thereof.

[0032] In certain embodiments, the molecular weight of the oxidized polysaccharides is from about 1,000 Da to about 100,000 Da.

[0033] In certain embodiments, the degree of functionalization of the oxidized polysaccharide is from about 10% to about 75%.

[0034] In certain embodiments, the oxidized polysaccharide comprises between 2 and 100 aldehyde moieties.

[0035] In certain embodiments, the oxidized polysaccharide comprises between 40 and 80 aldehyde moieties.

[0036] In certain embodiments, the oxidized polysaccharide comprises between 50 and 70 aldehyde moieties.

[0037] In certain embodiments, the oxidized polysaccharide is dextran.

[0038] In certain embodiments, the molecular weight of the dextran is about 10 kDa.

[0039] In certain embodiments, about 50% of the hydroxyl groups of the dextran are oxidized to aldehydes.

[0040] In certain embodiments, the adhesive material is flexible enough to bend through 180°. In certain embodiments, a 3 cm long sample of the adhesive material is flexible enough to bend through 180°.

[0041] In one embodiment, a method for treating, adhering, or sealing one or more biological tissues or artificial materials is disclosed, the method comprising: Providing a block copolymer comprising one or more polyethylene oxide (PEO) blocks, one or more polypropylene oxide (PPO) blocks, and at least one primary amine group; providing a second component comprising an oxidized polysaccharide comprising at least two aldehyde moieties; Producing an adhesive formulation by combining the first component and the second component; contacting the adhesive formulation with one or more biological tissue surfaces; and Allowing the adhesive formulation to harden in adhesion to one or more biological tissue surfaces. Includes.

[0042] In certain embodiments, the method further comprises adjusting a concentration of the first component or the second component to compensate for a characteristic of the biological tissue.

[0043] In certain embodiments, the molecular weight of the block copolymer of the above method is from about 1,000 Da to about 25,000 Da, or from about 1,000 to about 20,000 Da.

[0044] In certain embodiments, the block copolymer of the above method is inverse thermosensitive.

[0045] In certain embodiments, the block copolymer of the above method comprises from 1 to about 50 primary amines.

[0046] In certain embodiments, the block copolymer of the above method comprises from 1 to about 25 primary amines.

[0047] In certain embodiments, the block copolymer of the above method has a PEO:PPO ratio of about 50:50 to about 80:20.

[0048] In certain embodiments, the block copolymer of the above method is FG-(poloxamer 188)-FG, FG-(poloxamer 237)-FG, FG-(poloxamer 338)-FG, FG-(poloxamer 407)-FG, or any combination thereof, where each FG independently represents H or a primary amine group, and at least one of the FGs is not H.

[0049] In certain embodiments, the primary amine groups of the above method are each independently 1,2-diaminoethane, tris(2-aminoethyl)amine, or low molecular weight (e.g., less than about 2,000 daltons, less than 1,000 daltons, less than 500 daltons, or less than 250 daltons) polyethyleneimine. For example, the primary amine groups are 1,2-diaminoethane residues, tris(2-aminoethyl)amine residues, or combinations thereof. In certain embodiments, the primary amine groups are provided by modification of poloxamer with 1,2-diaminoethane, tris(2-aminoethyl)amine, or combinations thereof.

[0050] In one embodiment, a method for treating, adhering, or sealing one or more biological tissues or artificial materials is disclosed, the method comprising: providing a first component comprising a functionalized poloxamer represented by FG-PEO-PPO-PEO-FG, where each FG independently represents H or a linker-amine moiety, and where at least one of the FGs is not H and each linker-amine moiety independently comprises at least one primary amine; providing a second component comprising an oxidized polysaccharide comprising at least two aldehyde moieties; Producing an adhesive formulation by combining the first component and the second component; contacting the adhesive formulation with one or more biological tissue surfaces; and Allowing the adhesive formulation to harden in adhesion to one or more biological tissue surfaces. Includes.

[0051] In certain embodiments, the method further comprises adjusting a concentration of the first component or the second component to compensate for a characteristic of the biological tissue.

[0052] In certain embodiments, the molecular weight of the functionalized poloxamer of the above method is from about 1,000 Da to about 25,000 Da, or from about 1,000 to about 20,000 Da.

[0053] In certain embodiments, the functionalized poloxamer of the above method is inverse thermolabile.

[0054] In certain embodiments, each linker-amine moiety of the above method comprises from 1 to about 50 primary amines.

[0055] In certain embodiments, each linker-amine moiety of the above method comprises from 1 to about 25 primary amines.

[0056] In certain embodiments, the functionalized poloxamer of the above method has a PEO:PPO ratio of about 50:50 to about 80:20.

[0057] In certain embodiments, the functionalized poloxamer of the above method is FG-(poloxamer 188)-FG, FG-(poloxamer 237)-FG, FG-(poloxamer 338)-FG, FG-(poloxamer 407)-FG, or any combination thereof.

[0058] In certain embodiments, the amine moieties of the linker-amine moieties of the above methods are each independently 1,2-diaminoethane, tris(2-aminoethyl)amine, or a low molecular weight (e.g., less than about 2,000 daltons, less than 1,000 daltons, less than 500 daltons, or less than 250 daltons) polyethyleneimine. For example, the amine moieties of the linker-amine moieties are 1,2-diaminoethane residues, tris(2-aminoethyl)amine residues, or combinations thereof. In certain embodiments, the amine moieties of the linker-amine moieties are provided by modification of a poloxamer with 1,2-diaminoethane, tris(2-aminoethyl)amine, or combinations thereof.

[0059] In certain embodiments, the oxidized polysaccharide of the above method has a molecular weight of about 1,000 Da to about 100,000 Da. Unless otherwise specified, the "molecular weight" of a polysaccharide refers to the number average molecular weight.

[0060] In certain embodiments, the degree of functionalization of the oxidized polysaccharide of the above method is from about 10% to about 75%.

[0061] In certain embodiments, the oxidized polysaccharide of the above method comprises between 2 and 100 aldehyde moieties.

[0062] In certain embodiments, the oxidized polysaccharide comprises between 40 and 80 aldehyde moieties.

[0063] In certain embodiments, the oxidized polysaccharide comprises between 50 and 70 aldehyde moieties.

[0064] In certain embodiments, the oxidized polysaccharide of the above method is dextran.

[0065] In certain embodiments, the molecular weight of the dextran is about 10 kDa.

[0066] In certain embodiments, about 50% of the hydroxyl groups of the dextran are oxidized to aldehydes.

[0067] In certain embodiments, the step of curing the adhesive formulation in adhesion to one or more biological tissue surfaces of the above method comprises covalent bonding, ionic bonding, mechanical interlocking, or a combination thereof.

[0068] In a particular embodiment, the gel time of the adhesive formulation is from about 1 second to about 100 seconds. The gel time is the time it takes for the adhesive formulation to become a gel. A gel is considered to have formed when the material no longer flows.

[0069] In certain embodiments, the gel time of the adhesive formulation is from about 40 seconds to about 80 seconds.

[0070] In certain embodiments, the adhesive formulation has a swelling value of about 30% to about 90%, the swelling value being the increase in mass of the material due to the intrusion of fluid into the voids between the polymer chains.

[0071] In certain embodiments, the adhesive formulation has a swelling value of about 40% to about 75%.

[0072] In certain embodiments, the first and second components of the above method are combined on the surface of one or more biological tissues; the adhesive formulation is formed on the surface of the one or more biological tissues; and optionally, the adhesive formulation is formed on a suture line associated with a PTFE or polyester vascular graft.

[0073] In certain embodiments, the one or more biological tissues of the above methods are human tissues.

[0074] In certain embodiments, the first component, the second component, or both, further comprise an additive selected from the group consisting of foaming agents, pH adjusters, thickening agents, antimicrobial agents, colorants, surfactants, and radio-opacifying agents.

[0075] In certain embodiments, the first component is an aqueous solution.

[0076] In certain embodiments, the second component is an aqueous solution.

[0077] In certain embodiments, the first component, the second component, or both components comprise an effective amount of at least one drug.

[0078] In certain embodiments, the method further comprises the step of diffusing at least one drug from the adhesive formulation into the biological tissue.

[0079] In certain embodiments, the adhesive formulation of the above method reduces inflammation, enhances healing, or both, of living tissue.

[0080] In certain embodiments, the biological tissue is gastrointestinal (GI) tissue.

[0081] In certain embodiments, the first and second components are provided using endoscopic techniques.

[0082] In one embodiment: a first component comprising a block copolymer comprising one or more polyethylene oxide (PEO) blocks, one or more polypropylene oxide (PPO) blocks, and at least one primary amine group; and a second component comprising an oxidized polysaccharide comprising at least two aldehyde moieties; a first syringe; and User manual A kit is disclosed comprising:

[0083] In one embodiment: a first component comprising a functionalized poloxamer represented by FG-PEO-PPO-PEO-FG, where each FG independently represents H or a linker-amine moiety, and where at least one of the FGs is not H and each linker-amine moiety independently comprises at least one primary amine; and a second component comprising an oxidized polysaccharide comprising at least two aldehyde moieties; a first syringe; and User manual A kit is disclosed comprising:

[0084] In certain embodiments, a first syringe of the kit comprises a first reservoir and a second reservoir; the first reservoir comprises a first component; the second reservoir comprises a second component; and optionally, the first syringe comprises a mixing tip or a spray nozzle.

[0085] In certain embodiments, the kit further comprises a second syringe.

[0086] In certain embodiments, a first component of the kit is stored in a first syringe and a second component is stored in a second syringe.

[0087] In certain embodiments, the first and second syringes of the kit each include a mixing tip or a spray nozzle.

[0088] In certain embodiments, the kit instructions explain how to select an appropriate concentration of the first component, or the second component, or both, to compensate for one or more biological tissue characteristics.

[0089] In certain embodiments, the first component, or the second component, or both, comprise a drug.

[0090] In one embodiment: A biocompatible adhesive material as disclosed herein; and An effective amount of at least one drug A drug delivery composition is disclosed, comprising: At least one drug is mixed with the biocompatible adhesive material.

[0091] In certain embodiments, the drug delivery composition contacts a living tissue.

[0092] In general, the adhesive formulation can be used on any internal or external biological tissue. The biological tissue can be human or other mammalian tissue. The biological tissue can be natural or artificially produced. The biological tissue can be skin, bone, eye, muscle, blood vessel, dura mater, or internal organs such as lung, intestine, heart, liver, etc. The adhesive formulation can be applied to a tissue site inside a human or other animal patient, for example, during surgery or other medical procedures. In one embodiment, the adhesive formulation is used to seal an anastomosis. In some embodiments, the adhesive formulation is used to adhere, seal, and / or treat wounds, lesions, or combinations thereof. For example, the adhesive formulation can be applied to slow-healing or troublesome wounds, such as those in patients suffering from diabetes.

[0093] In general, the adhesive materials and formulations disclosed herein can be used on any internal or external biological tissue. The biological tissue can be human or other mammalian tissue. The biological tissue can be natural or artificially produced. The biological tissue can be skin, bone, eye, muscle, blood vessel, or internal organs such as lung, intestine, heart, liver, etc.

[0094] The adhesive material and / or formulation can be applied to a tissue site within a human or other animal patient, for example, during surgery or other medical procedures. In one embodiment, the adhesive material is used to seal an anastomosis. In some embodiments, the adhesive formulation is used to adhere, seal and / or treat a wound, a lesion, or a combination thereof. For example, the adhesive formulation can be applied to slow-healing or troublesome wounds, such as in patients suffering from diabetes. In one embodiment, the adhesive formulation can be used to secure or assist in the fixation of medical implants, such as orthopedic implants, within a human or other animal patient. In some embodiments, the adhesive formulation is used to seal and protect lesions within the digestive tract, such as peptic ulcers or polyp removal lacerations.

[0095] Poloxamer Ingredients Generally, poloxamers can be made using any known method. In one embodiment, poloxamers are made by treating a starting poloxamer (e.g., Pluronic® F-68) having a terminal group containing at least one hydroxyl group with a multifunctional amine (e.g., polyethyleneimine) and a coupling agent (e.g., 1,1'-carbonyldiimidazole (CDI)) such that at least a portion of the surface groups contain at least one amine.

[0096] In certain embodiments, the poloxamer component or the first component is combined with a liquid to form a poloxamer component (first component) solution. In one embodiment, the poloxamer component solution is an aqueous solution. In one embodiment, the solution comprises water, phosphate buffered saline (PBS), Dulbecco's Modified Eagle's Medium (DMEM), borate buffer, carbonate buffer, or any combination thereof. In one embodiment, the concentration of the poloxamer component in the poloxamer component solution is about 5% to about 25% by weight. In another embodiment, the concentration of the poloxamer component in the poloxamer component solution is about 10% to about 20% by weight. In a further embodiment, the concentration of the poloxamer component in the poloxamer component solution is about 11% to about 15% by weight.

[0097] In some cases, the poloxamer component or poloxamer component solution may further comprise an additive. In general, the amount of additive may vary depending on the application, tissue type, concentration of the poloxamer component solution, type of poloxamer component, concentration of the oxidized polysaccharide component solution, and / or type of oxidized polysaccharide component. Examples of suitable additives include, but are not limited to, pH adjusters, thickeners, antimicrobial agents, colorants, surfactants, and radiopaque compounds. Specific examples of these types of additives are described herein. In one embodiment, the poloxamer component solution comprises a foaming additive.

[0098] In certain embodiments, the poloxamer component or poloxamer component solution comprises an effective amount of at least one drug. In such embodiments, the adhesive formulation can function as a matrix material for controlled release of the drug. The drug can be essentially any drug suitable for local, regional, or systemic administration from a volume of the adhesive formulation applied to one or more tissue sites of a patient. In one embodiment, the drug comprises a thrombogenic agent. Non-limiting examples of thrombogenic agents include thrombin, fibrinogen, homocysteine, estramustine, and combinations thereof. In another embodiment, the drug comprises an anti-inflammatory agent. Non-limiting examples of anti-inflammatory agents include indomethacin, salicylic acid acetate, ibuprofen, sulindac, piroxicam, naproxen, and combinations thereof. In yet another embodiment, the drug comprises an anti-tumor agent. In yet another embodiment, the drug is a drug for gene therapy. For example, the drug may comprise an siRNA molecule for fighting cancer. Other drugs are also contemplated.

[0099] In other specific embodiments, the poloxamer component or poloxamer component solution includes one or more cells. For example, the adhesive formulation can function as a matrix material to deliver cells to the tissue site to which the adhesive formulation is applied. In embodiments, the cells may include endothelial cells (EC), endothelial progenitor cells (EPC), hematopoietic stem cells, or other stem cells. In one embodiment, the cells can release factors to treat cardiovascular disease and / or reduce restenosis. Other types of cells are also contemplated.

[0100] Oxidized polysaccharide components Generally, the oxidized polysaccharide component or second component comprises an oxidized polysaccharide having one or more functional groups capable of reacting with one or more functional groups on the biological tissue and / or one or more functional groups on the poloxamer component. In these embodiments, the at least one polysaccharide may be linear, branched, or have both linear and branched sections in its structure. In general, the at least one polysaccharide may be natural, synthetic, or modified, for example, by crosslinking, changing the substituents on the polysaccharide, or both. In one embodiment, the at least one polysaccharide is plant-based. In another embodiment, the at least one polysaccharide is animal-based. In another embodiment, the at least one polysaccharide is bacterial-based. In yet another embodiment, the at least one polysaccharide is a combination of plant-based polysaccharides, animal-based polysaccharides, or bacterial-based polysaccharides. Non-limiting examples of polysaccharides include, but are not limited to, dextran, chitin, starch, agar, cellulose, hyaluronic acid, or combinations thereof.

[0101] In some embodiments, the oxidized polysaccharide comprises one or more functional groups that will react with one or more functional groups on the biological tissue and / or one or more functional groups on the poloxamer component, hi one embodiment, at least two or more of the functional groups incorporated into the structure of the oxidized polysaccharide are aldehydes.

[0102] In certain embodiments, the degree of functionalization of the oxidized polysaccharides can be adjusted. "Degree of functionalization" generally refers to the number or percentage of reactive groups on the oxidized polysaccharide that are substituted or converted to one or more desired functional groups. In one embodiment, the degree of functionalization is adjusted based on the type of tissue to which the adhesive is applied, the concentration of the components, and / or the type of oxidized polysaccharide or poloxamer used in the adhesive. In one embodiment, the degree of functionalization is from about 10% to about 75%. In another embodiment, the degree of functionalization is from about 15% to about 50%. In yet another embodiment, the degree of functionalization is from about 20% to about 30%.

[0103] In some embodiments, the oxidized polysaccharide contains two or more aldehyde functional groups at a desired percentage. In general, the oxidation can be carried out using any known means. For example, suitable oxidizing agents include, but are not limited to, periodates, hypochlorites, ozone, peroxides, hydroperoxides, persulfates, and percarbonates. In one embodiment, the oxidation is carried out using sodium periodate. Typically, the degree of functionalization can be varied by using different amounts of oxidizing agents.

[0104] In certain embodiments, the oxidized polysaccharide component or the second component is combined with a liquid to form an oxidized polysaccharide component solution or a second component solution. In one embodiment, the oxidized polysaccharide component solution is an aqueous solution. In one embodiment, the solution comprises water, PBS, DMEM, or any combination thereof.

[0105] Generally, the oxidized polysaccharide component solution may have any suitable concentration of the oxidized polysaccharide component. In one embodiment, the concentration of the oxidized polysaccharide component in the oxidized polysaccharide component solution is from about 5% to about 40% by weight. In another embodiment, the concentration of the oxidized polysaccharide component in the oxidized polysaccharide component solution is from about 5% to about 30% by weight. In yet another embodiment, the concentration of the oxidized polysaccharide component in the oxidized polysaccharide component solution is from about 5% to about 25% by weight. Typically, the concentration can be adjusted and / or tailored based on the particular application, tissue type, and / or type and concentration of poloxamer component used.

[0106] The oxidized polysaccharide component or oxidized polysaccharide component solution may also include one or more additives. In one embodiment, the additive is compatible with the oxidized polysaccharide component. In another embodiment, the additive does not contain a primary or secondary amine. In general, the amount of additive will vary depending on the application, tissue type, concentration of the oxidized polysaccharide component solution, and type of oxidized polysaccharide component and / or poloxamer component. Examples of suitable additives include, but are not limited to, pH adjusters, thickeners, antimicrobial agents, colorants, surfactants, and radiopaque compounds. In another embodiment, the oxidized polysaccharide component solution includes a foaming agent.

[0107] In certain embodiments, the pH adjuster is an acidic compound. Examples of acidic pH adjusters include, but are not limited to, carboxylic acids, inorganic acids, and sulfonic acids. In other embodiments, the pH adjuster is a basic compound. Examples of basic pH adjusters include, but are not limited to, hydroxides, alkoxides, nitrogen-containing compounds other than primary and secondary amines, basic carbonates, and basic phosphates.

[0108] Generally, the thickening agent can be selected from any known viscosity modifying compound, including, but not limited to, polysaccharides such as starch or hydroxyethyl cellulose and their derivatives.

[0109] In general, the surfactant may be any compound that reduces the surface tension of water. In one embodiment, the surfactant is an ionic surfactant, such as sodium lauryl sulfate. In another embodiment, the surfactant is a neutral surfactant. Examples of neutral surfactants include, but are not limited to, polyoxyethylene ethers, polyoxyethylene esters, and polyoxyethylene sorbitan.

[0110] In one embodiment, the radiopaque compound is barium sulfate, gold particles, or a combination thereof.

[0111] In certain embodiments, the oxidized polysaccharide component or oxidized polysaccharide component solution includes an effective amount of at least one drug. In such embodiments, the adhesive formulation can function as a matrix material for controlled release of the drug. The drug can be essentially any drug suitable for local, regional, or systemic administration from a volume of the adhesive formulation applied to one or more tissue sites of a patient. In one embodiment, the drug includes a thrombogenic agent. Non-limiting examples of thrombogenic agents include thrombin, fibrinogen, homocysteine, estramustine, and combinations thereof. In another embodiment, the drug includes an anti-inflammatory agent. Non-limiting examples of anti-inflammatory agents include indomethacin, salicylic acid acetate, ibuprofen, sulindac, piroxicam, naproxen, and combinations thereof. In yet another embodiment, the drug includes an anti-tumor agent. In yet another embodiment, the drug is a drug for gene therapy or cell therapy. For example, the drug may include an siRNA molecule to combat cancer. Other drugs are also contemplated.

[0112] In other specific embodiments, the oxidized polysaccharide component or oxidized polysaccharide component solution includes one or more cells. For example, the adhesive formulation can function as a matrix material for delivering cells to the tissue site to which the adhesive formulation is applied. In embodiments, the cells may include endothelial cells (ECs), endothelial progenitor cells (EPCs), hematopoietic stem cells, or other stem cells. In one embodiment, the cells can release factors to treat cardiovascular disease and / or reduce restenosis. Other types of cells are also contemplated.

[0113] Bioactive and Pharmaceutically Active Agents In certain embodiments, one or more bioactive agents can be incorporated into the biocompatible adhesive material of the present invention. Active agents that can be used in the composition of the present invention include growth factors such as transforming growth factor (TGF), fibroblast growth factor (FGF), platelet derived growth factor (PDGF), epidermal growth factor (EGF), connective tissue activated peptide (CTAP), bone morphogenetic factor, and biologically active analogs, fragments, and derivatives of these growth factors. Members of the transforming growth factor (TGF) supergene family, which are multifunctional regulatory proteins, are particularly preferred. Members of the TGF supergene family include transforming growth factor beta (e.g., TGF-β1, TGF-β2, TGF-β3); bone morphogenetic proteins (e.g., BMP-1, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9); heparin-binding growth factors (e.g., fibroblast growth factor (FGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF)); inhibins (e.g., inhibin A, inhibin B); growth differentiation factors (e.g., GDF-1); and activins (e.g., activin A, activin B, activin AB).

[0114] In addition to the bioactive agents mentioned above, numerous drugs are known in the art and may be used in the biocompatible adhesive material of the present invention. The term "pharmaceutical agent" includes, but is not limited to: medicaments; vitamins; mineral supplements; substances used in the treatment, prevention, diagnosis, cure, or mitigation of disease or illness; or substances that affect the structure or function of the body; or prodrugs that gain biological activity or become more active after being placed in a certain physiological environment.

[0115] Non-limiting examples of broad categories of useful pharmaceutical agents include the following therapeutic categories: anabolic agents, antacids, antiasthmatics, anticholesterol and antilipid agents, anticoagulants, anti-convulsants, antidiarrheals, anti-emetics, anti-infectives, anti-inflammatory agents, antimanic agents, anti-nauseants, antitumor agents, anti-obesity agents, antipyretics, analgesics, antispasmod ... agents), antithrombotic agents, antiuricemic agents, antianginal agents, antihistamines, antitussives, appetite suppressants, biologics, cerebrovascular dilators, coronary artery dilators, decongestants, diuretics, diagnostic agents, erythropoietic agents, expectorants, gastrointestinal sedatives, hyperglycemic agents, hypnotics, hypoglycemic agents, ion exchange resins, laxatives, mineral supplements, mucolytics, neuromuscular agents, peripheral vasodilators, psychotropic agents, sedatives, stimulants, thyroid and antithyroid agents, uterine relaxants, vitamins, and prodrugs.

[0116] More specifically, non-limiting examples of useful agents include the following therapeutic categories: analgesics, such as nonsteroidal anti-inflammatory drugs, opiate agonists, and salicylates; antihistamines, such as H1 blockers and H2 blockers; anthelmintics, antianaerobic agents, antibiotics, aminoglycoside antibiotics, antifungal antibiotics, cephalosporin antibiotics, macrolide antibiotics, various β-lactam antibiotics, penicillin antibiotics, quinolone antibiotics, sulfonamide antibiotics, tetracycline antibiotics, antimycobacterial agents, antituberculous antimycotics, ... anti-infectives, such as antibacterials, antiprotozoal agents, antimalarial antiprotozoal agents, antiviral agents, antiretroviral agents, scabicides, and urinary tract anti-infectives; anti-tumor agents, such as alkylating agents, nitrogen mustard alkylating agents, nitrosourea alkylating agents, antimetabolites, purine analog antimetabolites, pyrimidine analog antimetabolites, antineoplastic hormones, natural antineoplastic agents, antibiotic natural antineoplastic agents, and vinca alkaloid natural antineoplastic agents; anticholinergics, antimuscarinic anticholinergics, ergot alkaloids, parasympathomimetics, cholinergic agonists, autonomic agents such as parasympathomimetics of the class 1 agonist, parasympathomimetics of the class 1 cholinesterase inhibitor, sympatholytic agents, alpha-blocker sympatholytic agents, beta-blocker sympatholytic agents, sympathomimetics, and adrenergic agonist sympathomimetics; antianginal agents, beta-blocker antianginal agents, calcium channel blocker antianginal agents, nitrate antianginal agents, antiarrhythmic agents, cardiac glycoside antiarrhythmic agents, class I antiarrhythmic agents, class II antiarrhythmic agents, class III antiarrhythmic agents, class IV ... cardiovascular agents such as class III antiarrhythmic agents, class IV antiarrhythmic agents, antihypertensive agents, alpha blocker antihypertensive agents, angiotensin converting enzyme inhibitor (ACE inhibitor) antihypertensive agents, beta blocker antihypertensive agents, calcium channel blocker antihypertensive agents, centrally acting adrenergic antihypertensive agents, diuretic antihypertensive agents, peripheral vasodilator antihypertensive agents, hypolipidemic agents, bile acid sequestrant antihyperlipidemic agents, HMG-CoA reductase inhibitor antihyperlipidemic agents, inotropes, cardiac glycoside inotropes, and thrombolytic agents;Dermatological agents such as antihistamines, anti-inflammatory agents, corticosteroid anti-inflammatory agents, antipruritic / local anesthetic agents, topical anti-infective agents, antifungal topical anti-infective agents, antiviral topical anti-infective agents, and topical anti-tumor agents; electrolyte agents and renal agents such as acidifiers, alkalinizers, diuretics, carbonic anhydrase inhibitor diuretics, loop diuretics, osmotic diuretics, potassium sparing diuretics, thiazide diuretics, electrolyte replacement agents, and uricosuric agents; pancreatic enzymes and and enzymes such as thrombolytic enzymes; gastrointestinal agents such as antidiarrheals, antiemetics, gastrointestinal anti-inflammatory agents, salicylates, antacids, gastric acid pump inhibitors, gastric mucosal anti-ulcer agents, H2 blockers, gallstone dissolving agents, digestive agents, emetics, laxatives, stool softeners, and gastrointestinal motility enhancers; inhalation anesthetics, halogenated inhalation anesthetics, intravenous anesthetics, barbiturates, benzodiazepines, and opiate agonists. hematological agents such as antianemic agents, hematopoietic antianemic agents, coagulants, anticoagulants, hemostatic coagulants, platelet inhibitor coagulants, thrombolytic enzyme coagulants, and plasma expanders; abortifacients, adrenal acting agents, corticosteroid adrenal acting agents, androgens, antiandrogens, antidiabetic agents, sulfonylurea antidiabetic agents, antihypoglycemic agents, oral contraceptives, progestin contraceptives, estrogens, pregnancy promoters, labor inducers, parathyroid acting agents immunobiological agents such as immunoglobulins, immunosuppressants, toxoids, and vaccines; local anesthetics such as amide local anesthetics and ester local anesthetics; musculoskeletal agents such as anti-gout anti-inflammatory agents, corticosteroid anti-inflammatory agents, gold compound anti-inflammatory agents, immunosuppressive anti-inflammatory agents, nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, skeletal muscle relaxants, neuromuscular blocking agent skeletal muscle relaxants, and reverse neuromuscular blocking agent skeletal muscle relaxants; neurological agents such as anticonvulsants, barbiturates anticonvulsants, benzodiazepines anticonvulsants, antimigraine agents, antiparkinsonian agents, antivertigo agents, opiate agonists, and opiate antagonists;Ophthalmic active agents such as antiglaucoma agents, beta-blocker antiglaucoma agents, miotic antiglaucoma agents, mydriatic agents, adrenergic mydriatic agents, antimuscarinic mydriatic agents, ophthalmic anesthetic agents, ophthalmic anti-infective agents, ophthalmic aminoglycoside anti-infective agents, ophthalmic macrolide anti-infective agents, ophthalmic quinolone anti-infective agents, ophthalmic sulfonamide anti-infective agents, ophthalmic tetracycline anti-infective agents, ophthalmic anti-inflammatory agents, ophthalmic corticosteroid anti-inflammatory agents, and ophthalmic nonsteroidal anti-inflammatory agents (NSAIDs); antidepressants, heterocyclic antidepressants, monoamine oxidase inhibitors (MAOIs), selective serotonin re-uptake inhibitors (SRAs), psychotropic agents such as SSRIs, tricyclic antidepressants, antimanics, antipsychotics, phenothiazine antipsychotics, anxiolytics, sedatives and hypnotics, barbiturates, benzodiazepines, sedatives and hypnotics, and psychostimulants; respiratory agents such as antitussives, bronchodilators, adrenergic bronchodilators, antimuscarinic bronchodilators, expectorants, mucolytics, respiratory anti-inflammatory agents, and respiratory corticosteroid anti-inflammatory agents; toxicological agents such as detoxifiers, heavy metal antagonists / chelators, drug abuse agents, drug abuse deterrents, and drug abuse withdrawal agents; minerals; and vitamins such as vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, vitamin K.

[0117] Preferred classes of useful drugs from the above categories include: (1) nonsteroidal anti-inflammatory drug (NSAID) analgesics, such as diclofenac, ibuprofen, ketoprofen, and naproxen; (2) opiate agonist analgesics, such as codeine, fentanyl, hydromorphone, and morphine; (3) salicylate analgesics, such as aspirin (ASA) (enteric coated ASA); (4) H1 blocker antihistamines, such as clemastine and terfenadine; (5) cimetidine, famotidine, nizat ... (6) anti-infective agents such as mupirocin; (7) anti-anaerobic anti-infective agents such as chloramphenicol and clindamycin; (8) anti-fungal antibiotic anti-infective agents such as amphotericin B, clotrimazole, fluconazole, and ketoconazole; (9) macrolide antibiotic anti-infective agents such as azithromycin and erythromycin; (10) various β-lactam antibiotic anti-infective agents such as aztreonam and imipenem; (11) nafcillin (11) penicillin antibiotic anti-infectives such as oxacillin, penicillin G, and penicillin V; (12) quinolone antibiotic anti-infectives such as ciprofloxacin and norfloxacin; (13) tetracycline antibiotic anti-infectives such as doxycycline, minocycline, and tetracycline; (14) antituberculous antimycobacterial anti-infectives such as isoniazid (INH) and rifampin; (15) antiprotozoal anti-infectives such as atovaquone and dapsone; (16) antimalarial antiprotozoal anti-infectives such as chloroquine and pyrimethamine; (17) anti-retroviral anti-infective agents, such as ritonavir and zidovudine; (18) anti-viral anti-infective agents, such as acyclovir, ganciclovir, interferon alpha, and rimantadine; (19) alkylating agent anti-tumor agents, such as carboplatin and cisplatin; (20) nitrosourea alkylating agent anti-tumor agents, such as carmustine (BCNU); (21) antimetabolite anti-tumor agents, such as methotrexate; (22) pyrimidine analog antimetabolite anti-tumor agents, such as fluorouracil (5-FU) and gemcitabine;(23) antitumor hormones such as goserelin, leuprolide, and tamoxifen; (24) natural antitumor agents such as aldesleukin, interleukin-2, docetaxel, etoposide (VP-16), interferon α, paclitaxel, and tretinoin (ATRA); (25) antibiotic-based natural antitumor agents such as bleomycin, dactinomycin, daunorubicin, doxorubicin, and mitomycin; (26) vinca alkaloid-based natural antitumor agents such as vinblastine and vincristine; (27) autonomic agents such as nicotine. (28) anticholinergic autonomic agents such as benztropine and trihexyphenidyl; (29) antimuscarinic anticholinergic autonomic agents such as atropine and oxybutynin; (30) ergot alkaloid autonomic agents such as bromocriptine; (31) cholinergic parasympathomimetics such as pilocarpine; (32) cholinesterase inhibitor parasympathomimetics such as pyridostigmine; (33) alpha-blocker sympatholytic agents such as prazosin; (34) beta-blocker sympatholytic agents such as atenolol; (35) albuterol and dobutamine (36) cardiovascular agents such as aspirin (ASA) (enteric coated ASA); (37) beta-blocker antianginal agents such as atenolol and propranolol; (38) calcium channel blocker antianginal agents such as nifedipine and verapamil; (39) nitrate antianginal agents such as isosorbide dinitrate (ISDN); (40) cardiac glycoside antiarrhythmic agents such as digoxin; (41) class I antiarrhythmic agents such as lidocaine, mexiletine, phenytoin, procainamide, and quinidine; (42) atenolol (43) Class II antiarrhythmics such as amiodarone; (44) Class IV antiarrhythmics such as diltiazem and verapamil; (45) alpha-blocker antihypertensives such as prazosin; (46) angiotensin-converting enzyme inhibitor (ACE inhibitor) antihypertensives such as captopril and enalapril; (47) beta-blocker antihypertensives such as atenolol, metoprolol, nadolol, and propranolol; (48) calcium channel blocker antihypertensives such as diltiazem and nifedipine;(49) centrally acting adrenergic antihypertensives such as clonidine and methyldopa; (50) diuretic antihypertensives such as amiloride, furosemide, hydrochlorothiazide (HCTZ), and spironolactone; (51) peripheral vasodilator antihypertensives such as hydralazine and minoxidil; (52) hypolipidemics such as gemfibrozil and probucol; (53) bile acid sequestrant hypolipidemics such as cholestyramine; (54) HMG-CoA reductase inhibitor hypolipidemics such as lovastatin and pravastatin; (55) inotropes such as amrinone, dobutamine, and dopamine. (56) cardiac glycoside inotropes such as digoxin; (57) thrombolytic agents such as alteplase (TPA), anistreplase, streptokinase, and urokinase; (58) dermatological agents such as colchicine, isotretinoin, methotrexate, minoxidil, and tretinoin (ATRA); (59) dermatological corticosteroid anti-inflammatory agents such as betamethasone and dexamethasone; (60) topical antifungal anti-infective agents such as amphotericin B, clotrimazole, miconazole, and nystatin; (61) antiviral agents such as acyclovir. (62) topical anti-infectives such as fluorouracil (5-FU); (63) electrolytes and renal agents such as lactulose; (64) loop diuretics such as furosemide; (65) potassium-sparing diuretics such as triamterene; (66) thiazide diuretics such as hydrochlorothiazide (HCTZ); (67) uricosurics such as probenecid; (68) enzymes such as RNase and DNase; (69) thrombolytic enzymes such as alteplase, anistreplase, streptokinase, and urokinase; (70) antiemetics such as prochlorperazine; (71) sulfonamide; (72) gastrointestinal anti-inflammatory salicylates such as acetazolidine; (73) H2 blocker anti-ulcer agents such as cimetidine, famotidine, nizatidine, and ranitidine; (74) digestive agents such as pancrelipase; (75) gastrointestinal motility enhancers such as erythromycin; (76) opiate agonist intravenous anesthetics such as fentanyl; (77) hematopoietic antianemic agents such as erythropoietin, filgrastim (G-CSF), and sargramostim (GM-CSF); (78) coagulants such as antihemophilic factor 1-10 (AHF1-10);(79) Anticoagulants such as warfarin; (80) Thrombolytic enzyme coagulants such as alteplase, anistreplase, streptokinase, and urokinase; (81) Hormones and hormone regulators such as bromocriptine; (82) Abortion drugs such as methotrexate; (83) Antidiabetic drugs such as insulin; (84) Oral contraceptives such as estrogens and progestins; (85) Progestin contraceptives such as levonorgestrel and norgestrel; (86) Conjugated estrogens, diethylstilbestrol (DES), estrogens (estradiol, estradiol), (87) estrogens, such as clomiphene, human chorionic gonadatropin (HCG), and menotropins; (88) parathyroid agonists, such as calcitonin; (89) pituitary hormones, such as desmopressin, goserelin, oxytocin, and vasopressin (ADH); (90) progestins, such as medroxyprogesterone, norethindrone, and progesterone; (91) thyroid hormones, such as levothyroxine; (92) immunobiological agents, such as interferon beta-1b and interferon gamma-1b. (93) Immunoglobulins, such as immunoglobulin IM, IMIG, IGIM, and immunoglobulin IV, IVIG, and IGIV; (94) Amide local anesthetics, such as lidocaine; (95) Ester local anesthetics, such as benzocaine and procaine; (96) Musculoskeletal corticosteroid anti-inflammatory agents, such as beclomethasone, betamethasone, cortisone, dexamethasone, hydrocortisone, and prednisone; (97) Musculoskeletal anti-inflammatory immunosuppressants, such as azathioprine, cyclophosphamide, and methotrexate; (98) Diclofenac, ibuprofen, Nonsteroidal anti-inflammatory drugs (NSAIDs) for musculoskeletal use, such as ketoprofen, ketorolac, and naproxen; (99) skeletal muscle relaxants, such as baclofen, cyclobenzaprine, and diazepam; (100) reverse neuromuscular blockers skeletal muscle relaxants, such as pyridostigmine; (101) neurological agents, such as nimodipine, riluzole, tacrine, and ticlopidine; (102) anticonvulsants, such as carbamazepine, gabapentin, lamotrigine, phenytoin, and valproic acid; (103) barbiturate anticonvulsants, such as phenobarbital and primidone;(104) Benzodiazepine anticonvulsants such as clonazepam, diazepam, and lorazepam; (105) Antiparkinsonian drugs such as bromocriptine, levodopa, carbidopa, and pergolide; (106) Antivertigo drugs such as meclizine; (107) Opiate agonists such as codeine, fentanyl, hydromorphone, methadone, and morphine; (108) Opiate antagonists such as naloxone; (109) β-blocker antiglaucoma drugs such as timolol; (110) Miotic antidiabetics such as pilocarpine. Glaucoma drugs; (111) ophthalmic aminoglycoside anti-infectives, such as gentamicin, neomycin, and tobramycin; (112) ophthalmic quinolone anti-infectives, such as ciprofloxacin, norfloxacin, and ofloxacin; (113) ophthalmic corticosteroid anti-inflammatory drugs, such as dexamethasone and prednisolone; (114) ophthalmic non-steroidal anti-inflammatory drugs (NSAIDs), such as diclofenac; (115) antipsychotics, such as clozapine, haloperidol, and risperidone. (116) benzodiazepine anxiolytics, sedatives and hypnotics such as clonazepam, diazepam, lorazepam, oxazepam and prazepam; (117) psychostimulants such as methylphenidate and pemoline; (118) cough suppressants such as codeine; (119) bronchodilators such as theophylline; (120) adrenergic bronchodilators such as albuterol; (121) respiratory corticosteroid anti-inflammatory agents such as dexamethasone; (122) lytics such as flumazenil and naloxone. poisons; (123) heavy metal antagonists / chelators such as penicillamine; (124) drug abuse deterrents such as disulfiram, naltrexone, and nicotine; (125) drug abuse withdrawal agents such as bromocriptine; (126) minerals such as iron, calcium, and magnesium; (127) vitamin B compounds such as cyanocobalamin (vitamin B12) and niacin (vitamin B3); (128) vitamin C compounds such as ascorbic acid; and (129) vitamin D compounds such as calcitriol.

[0118] In addition to the above, the following less common drugs may be used: chlorhexidine; estradiol cypionate in oil; estradiol valerate in oil; flurbiprofen; flurbiprofen sodium; ivermectin; levodopa; nafarelin; and somatropin. Additionally, the following drugs may be used: recombinant beta-glucan; bovine immunoglobulin concentrate; bovine superoxide dismutase; a formulation containing fluorouracil, epinephrine, and bovine collagen; recombinant hirudin (r-Hir), an HIV-1 immunogen; human anti-TAC antibody; recombinant human growth hormone (r-hGH); recombinant human hemoglobin (r-Hb); recombinant human mecasermin (r-IGF-1); recombinant interferon beta-1a; lenograstim (G-CSF); olanzapine; recombinant thyroid stimulating hormone (r-TSH); and topotecan.

[0119] Additionally, the following products for intravenous administration may be used: acyclovir sodium; aldesleukin; atenolol; bleomycin sulfate, human calcitonin; salmon calcitonin; carboplatin; carmustine; dactinomycin, daunorubicin HCl; docetaxel; doxorubicin HCl; epoetin alfa; etoposide (VP-16); fluorouracil (5-FU); ganciclovir sodium; gentamicin sulfate; interferon alpha; leuprorelin acetate; meperidine HCl; methadone HCl; methotrexate sodium; paclitaxel; ranitidine HCl; vinblastine sulfate; and zidovudine (AZT).

[0120] Further examples of useful agents from the above categories include: (a) anti-tumor agents, such as androgen inhibitors, antimetabolites, cytotoxic agents, and immunomodulatory agents; (b) dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentane citrate, and clofedanol hydrochloride, etc. Cough suppressants; (c) antihistamines such as chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, and phenyltoloxamine citrate; (d) Decongestants such as phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, and ephedrine; (e) various alkaloids, such as codeine phosphate, codeine sulfate, and morphine; (f) Mineral supplements, such as potassium chloride, zinc chloride, calcium carbonate, magnesium oxide, and other alkali metal and alkaline earth metal salts; (g) ion exchange resins such as cholestyramine; (h) Antiarrhythmic drugs such as N-acetylprocainamide; (i) Antipyretics and analgesics, such as acetaminophen, aspirin, and ibuprofen; (j) appetite suppressants, such as phenyl-propanolamine hydrochloride or caffeine; (k) expectorants such as guaifenesin; (1) Antacids such as aluminum hydroxide and magnesium hydroxide; (m) Peptides, polypeptides, proteins and amino acids, hormones, interferons or cytokines, and interleukins 1 to 18 (including variants and analogs), RNase, DNase, luteinizing hormone releasing hormone (LHRH) and analogs, gonadotropin releasing hormone (GnRH), transforming growth factor-β (TGF-β), fibroblast growth factor (FGF), tumor necrosis factor-α and β (TNF-α and β), nerve growth factor (NGF), growth hormone releasing hormone (GHRR), and other similar compounds. biological agents, such as growth factor receptor agonist (GHRF), epidermal growth factor (EGF), fibroblast growth factor homologous factor (FGFHF), hepatocyte growth factor (HGF), insulin growth factor (IGF), invasion inhibitory factor-2 (IIF-2), bone morphogenetic proteins 1-7 (BMP1-7), somatostatin, thymosin alpha 1, gamma globulin, superoxide dismutase (SOD), complement factors, hGH, tPA, calcitonin, ANF, EPO, and other biologically active peptide compounds, such as insulin; and (n) Anti-infective agents, such as anti-fungals, anti-virals, disinfectants, and antibiotics.

[0121] Alternatively, the drug may be a radiosensitizer, such as: metoclopramide, Sensamide or neusensamide (Oxigene); Profilomycin (Vion); RSR13 (Allos); Thymitaq (Agouron), Ethanidazole or Iobenguane (Nycomed); Gadolinium Texaphyrin (Pharmacyclics); BuDR / Broxine (NeoPharm); IPdR (Sparta); CR2412 (Cell Therapeutic); LlX (Terrapin); etc. Preferably, the biologically active agent is selected from the group consisting of peptides, polypeptides, proteins, amino acids, polysaccharides, growth factors, hormones, anti-angiogenic factors, interferons or cytokines, and prodrugs. In particularly preferred embodiments, the biologically active agent is a therapeutic drug or prodrug, most preferably a drug selected from the group consisting of chemotherapeutic agents and other anti-tumor agents such as paclitaxel, antibiotics, antivirals, antifungals, anti-inflammatory agents and anticoagulants.

[0122] The biologically active agent is used in a therapeutically effective amount. The effective amount of biologically active agent will depend on the particular material used, but an amount of about 1% to about 65% of the biologically active agent may be desirable. For certain biologically active agents, lesser amounts may be used to achieve an effective level of treatment.

[0123] Adhesive materials or adhesive preparations In general, the adhesive materials or adhesive formulations described herein can be formed by combining the oxidized polysaccharide component or oxidized polysaccharide component solution with the poloxamer component or poloxamer component solution in any manner. In some embodiments, the oxidized polysaccharide component or oxidized polysaccharide component solution and the poloxamer component or poloxamer component solution are combined prior to contacting the biological tissue with the adhesive formulation. In other embodiments, the oxidized polysaccharide component or oxidized polysaccharide component solution and the poloxamer component or poloxamer component solution are combined in any order on the biological tissue. In further embodiments, the oxidized polysaccharide component or oxidized polysaccharide component solution is applied to a first biological tissue, the poloxamer component or poloxamer component solution is applied to a second biological tissue, and the first biological tissue is contacted with the second biological tissue. In yet a further embodiment, the oxidized polysaccharide component or an oxidized polysaccharide component solution is applied to a first region of a biological tissue and the poloxamer component or a poloxamer component solution is applied to a second region of a biological tissue, and the first region is contacted with the second region.

[0124] In general, the adhesive formulation may be applied to one or more biological tissues as an adhesive, a sealant, and / or a treatment. The one or more biological tissues may be diseased or healthy. In one embodiment, the adhesive formulation is applied to one or more biological tissues as an adhesive. In another embodiment, the adhesive formulation is applied to one or more biological tissues as a sealant. In a further embodiment, the adhesive formulation is applied to one or more biological tissues as a treatment. In an additional embodiment, the adhesive formulation is applied to one or more biological tissues as both an adhesive and a sealant. In yet another embodiment, the adhesive formulation is applied to one or more biological tissues as both an adhesive and a treatment. In yet another embodiment, the adhesive formulation is applied to one or more biological tissues as a sealant and a treatment. In yet a further embodiment, the adhesive formulation is applied to one or more biological tissues as an adhesive, a sealant, and a treatment.

[0125] As used herein, an adhesive material or adhesive formulation is a "treatment" if it improves the response of at least one biological tissue to which it is applied. In some embodiments, the improved response is a reduction in overall inflammation, an improvement in the specific response at the wound site / tissue and adhesive formulation interface, enhanced healing, or a combination thereof. As used herein, the phrase "lessening overall inflammation" refers to an improvement in histological scores reflecting the severity of inflammation. As used herein, the phrase "improving the specific response at the wound site / interface of the tissue and adhesive formulation" refers to an improvement in histological scores reflecting the severity of serosal neutrophils. As used herein, the phrase "enhancing healing" refers to an improvement in histological scores reflecting the severity of serosal fibrosis.

[0126] After contacting one or more biological tissues, the adhesive formulation may be given sufficient time to harden or gel. When the adhesive formulation "hardens" or "gels", as these terms are used herein, these terms mean that the reactive groups on the oxidized polysaccharide component, the poloxamer component, and one or more biological tissues have undergone one or more reactions. When the adhesive formulation "cures" or "gels" herein, this means that the reactive groups on the oxidized polysaccharide component, the poloxamer component, and one or more biological tissues have undergone one or more reactions. Without wishing to be bound by any particular theory, it is believed that the adhesive formulation described herein is effective because the oxidized polysaccharide component reacts with both the poloxamer component and the surface of the biological tissue. In certain embodiments, the aldehyde functional group of the oxidized polysaccharide component reacts with the amine on the poloxamer component and the biological tissue to form an imine bond. In these embodiments, it is believed that the amines on the poloxamer component react with many of the aldehydes on the oxidized polysaccharide component, thereby reducing the toxicity of the adhesive formulation and improving its biocompatibility. Typically, the time required for the adhesive formulation to cure or gel will vary based on a number of factors, including, but not limited to, the properties of the oxidized polysaccharide component and / or the poloxamer component, the concentration of the oxidized polysaccharide component solution and / or the poloxamer component solution, and the properties of one or more biological tissues. In embodiments, the adhesive formulation will cure to a sufficient degree to provide the desired bond or seal immediately after the components are combined. The gelling or curing time should be such that the mixture of components can be delivered to the target area in a fluid form before becoming too viscous or solidifying, and can then be rapidly cured once applied to the target area. In one embodiment, the gelling or curing time is less than 120 seconds. In another embodiment, the gelling or curing time is between 1 and 100 seconds. In certain embodiments, the gelling or curing time is between 3 and 60 seconds.

[0127] Adhesive Preparation Kit In another aspect, a kit is provided comprising a first part comprising an oxidized polysaccharide component or an oxidized polysaccharide component solution and a second part comprising a poloxamer component or a poloxamer component solution. The kit may further comprise an applicator or other device means, such as a multi-compartment syringe, for storage, combination and delivery of the two parts and / or the resulting adhesive formulation to a tissue site.

[0128] In certain embodiments, the kit comprises at least one syringe. In one embodiment, the syringe comprises separate reservoirs for the oxidized polysaccharide component solution and the poloxamer component solution. The syringe may also comprise a mixing tip or a spray nozzle or a delivery catheter that combines the two solutions when the plunger is pressed. The mixing tip may be releasably securable to the syringe (to allow for mixing tip replacement) or may comprise a static mixer. In some embodiments, the reservoirs in the syringe may have different sizes or contain different volumes of solutions. In other embodiments, the reservoirs in the syringe may have the same size or contain the same volumes of solutions. In further embodiments, one reservoir may contain part 1 of the foaming composition described above, and a second reservoir may contain part 2 of the foaming composition.

[0129] In a further embodiment, one or more of the syringe reservoirs may be removable, in which case the removable reservoir may be replaced with a reservoir containing the desired concentration of the oxidized polysaccharide or poloxamer component solution.

[0130] In certain preferred embodiments, the kits are sterile. For example, the components of the kits can be packaged together, for example, in a tray, pouch, and / or box. The packaged kits can be sterilized using known techniques, such as electron beam irradiation, gamma irradiation, ethylene oxide sterilization, or other suitable techniques.

[0131] definition Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those of ordinary skill in the art. Overall, the nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein are those known and commonly used in the art.

[0132] The methods and techniques of the present disclosure are generally performed according to methods known in the art and as described in various general and more specific references cited and discussed throughout the specification, unless otherwise indicated. See, for example, "Principles of Neural Science", McGraw-Hill Medical, New York, NY (2000); Motulsky, "Intuitive Biostatistics", Oxford University Press, Inc. (1995); Lodish et al., "Molecular Cell Biology, 4th ed.", WH Freeman & Co., New York (2000); Griffiths et al., "Introduction to Genetic Analysis, 7th ed.", WH Freeman & Co., NY (1999); and Gilbert et al., "Developmental Biology, 6th ed.", Sinauer Associates, Inc., Sunderland, MA (2000).

[0133] Chemical terms used herein, unless otherwise defined herein, are used in accordance with conventional usage in the art, as exemplified in "The McGraw-Hill Dictionary of Chemical Terms", Parker S., Ed., McGraw-Hill, San Francisco, CA (1985).

[0134] All of the above and any other publications, patents, and published patent applications mentioned in this application are specifically incorporated by reference into this application. In the case of conflict, the present specification, including specific definitions, will control.

[0135] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "optionally substituted alkyl" refers to cases where the alkyl may be substituted and cases where the alkyl is not substituted.

[0136] The substituents and substitution patterns of the compounds of the present invention can be selected by one skilled in the art to provide chemically stable compounds that can be readily synthesized from readily available starting materials by techniques known in the art and the methods described below. When a substituent is itself substituted with more than one group, it is understood that these multiple groups can be on the same carbon or on different carbons, so long as a stable structure is obtained.

[0137] Articles such as "a," "an," and "the" can mean one or more, unless indicated otherwise or the context makes clear otherwise. A claim or description including "or" between one or more members of a group is deemed to be satisfied if one, more than one, or all of the members of the group are present, employed, or otherwise relevant in a given product or process, unless indicated otherwise or the context makes clear otherwise. The invention includes embodiments in which only one member of the group is present, employed, or otherwise relevant in a given product or process. The invention includes embodiments in which two or more, or all of the members of the group are present, employed, or otherwise relevant in a given product or process.

[0138] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., male or female of any age, e.g., a pediatric subject (e.g., infant, juvenile, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly adult), and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0139] "Effective amount" means the amount of a compound that, when administered to a subject for treating or preventing a disease, is sufficient to effect treatment or prevention. The "effective amount" may vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject being treated. "Therapeutically effective amount" refers to an amount effective for therapeutic treatment.

[0140] "Preventing" or "prevention" or "prophylactic treatment" refers to reducing the risk of acquiring or developing a disease or disorder (i.e., preventing at least one clinical symptom of the disease from developing prior to the onset of the disease in a subject who has not yet been exposed to a causative agent of the disease or who is susceptible to the disease).

[0141] The term "prophylaxis" is related to "prevention" and refers to measures or procedures aimed at preventing rather than treating or curing a disease. Non-limiting examples of prophylactic measures include: administration of vaccines; administration of low molecular weight heparin to hospitalized patients at risk of blood clots, for example due to immobilization, and administration of antimalarial drugs such as chloroquine before visiting areas where malaria is endemic or where there is a high risk of malaria infection.

[0142] "Treating" or "treatment" or "therapeutic treatment" of any disease or disorder, in one embodiment, refers to ameliorating the disease or disorder (i.e., halting the progression of the disease or reducing at least one sign, degree, or severity of the clinical symptoms of the disease). In another embodiment, "treating" or "treatment" refers to improving at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to physical modulation of the disease or disorder (e.g., stabilization of a discernible symptom), physiological modulation (e.g., stabilization of a physical parameter), or both. In a further embodiment, "treating" or "treatment" refers to slowing the progression of the disease.

[0143] As used herein, the term "adhering" generally refers to attaching two or more biological tissues, or two or more regions of one biological tissue, permanently or temporarily. As used herein, the term "sealing" generally refers to at least partially covering or at least partially filling one or more sites, such as wounds, of one or more biological tissues. As used herein, the term "treating" generally refers to improving the response of at least one biological tissue to which one or more adhesive formulations are applied. In some embodiments, the "response" that is improved or enhanced includes inflammation, healing, or both.

[0144] Unless otherwise indicated, the description or name of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures thereof, racemates, etc. Methods for the determination of stereochemistry and separation of stereoisomers are known in the art.

[0145] Those of ordinary skill in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocycle, whether aromatic or non-aromatic, is determined by the size of the ring, the degree of unsaturation, and the valence of the heteroatoms. In general, a heterocycle can have from 1 to 4 heteroatoms, so long as the heterocycle is chemically feasible and stable. EXAMPLES

[0146] In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are provided to illustrate the compounds, compositions, materials, devices, and methods provided herein, and should not be construed as limiting the scope thereof.

[0147] Example 1: Amine-terminated poloxamer

[0148] The first component of the present disclosure consists of an aqueous solution of homobifunctionalized amine-terminated poloxamers. Poloxamers are linear polymers with the structure ABA(FG-PEO-PPO-PEO-FG), where each FG independently represents H or a linker-amine moiety, and at least one of the FGs is not H. The triblock structure of the poloxamers confers temperature sensitivity to this family of polymers.

[0149] Poloxamers are functionalized with a variety of amine-containing molecules that provide a family of polymers with varying numbers of amine end groups. Table 1 shows some examples of amines used to modify poloxamers.

[0150] [Table 1]

[0151] [ka]

[0152] Poloxamers functionalized with various amine-containing molecules were synthesized according to the following synthetic procedure, as shown in Scheme 1: 1. Dissolve 16.8 g of Pluronic® F-68 (2 mmol) in 50 mL of acetonitrile (ACN). 2. Dissolve 3.25 g (20 mmol) of 1,1'-carbonyldiimidazole (CDI) in 40 mL of ACN and add this dropwise to the Pluronic® F-68 solution while maintaining an inert atmosphere and stirring. Allow CDI to activate the hydroxyl groups of the Pluronic® at room temperature (rt) for 2 hours (h). 3. In a round bottom flask, dissolve 40 g of polyethyleneimine (PEI) in 40 mL of ACN. Slowly drip (1 mL / min) the activated Pluronic® solution into the stirring PEI. Allow to react overnight at room temperature. 4. The ACN is evaporated from the reaction mixture (40° C. / 90 mBar) and the resulting solid is redissolved in 100 mL of H2O. 5. Extensive dialysis is performed against water using Spectrum membrane MWCO 3KDa to remove unreacted PEI and CDI salts. After 7 days of dialysis, the purified solution is lyophilized to obtain the modified homobifunctional Plu-68-PEI.

[0153] Different types of poloxamers were used to create a family of polymers with a wide range of biological and mechanical properties. Table 2 shows some examples of poloxamers offered with different molecular weights and hydrophilic / hydrophobic ratios.

[0154] [Table 2]

[0155] Linear poloxamer (polyethylene oxide-polypropylene oxide-polyethylene oxide, PEO-PPO-PEO) polymers with different molecular weights and PEO:PPO ratios have end groups functionalized with polyamine molecules (Figure 1). The different PEO:PPO ratios and total molecular weights give each of these polymers a specific transition temperature between the various molecular cluster states.

[0156] Example 2: Crosslinking Agent Oxidation of polysaccharides such as dextran generates aldehyde groups along its backbone. When mixed at the appropriate pH, the aldehydes present in the oxidized dextran can readily react with the terminal amines of the modified poloxamer. The reaction of amine-modified Pluronic® with oxidized dextran produces an adhesive, biodegradable, biocompatible hydrogel. The aldehydes and amines form a stable, yet reversible imine bond. The reversibility of this chemical bond makes the material biodegradable and therefore implantable in the body.

[0157] Aldehyde dextran is obtained by oxidizing 10 kDa dextran with sodium periodate. By adjusting the amount of sodium periodate, an oxidation degree of approximately 40-50% is achieved.

[0158] Example 3: Hydrogel synthesis using poloxamer 188 45% oxidized dextran is reacted with poloxamer 188 modified with low molecular weight polyethyleneimine. The oxidized dextran is dissolved in water or a biocompatible aqueous buffer to obtain a 20% w / v solution. PEI-poloxamer-188-PEI is dissolved in water or a biocompatible aqueous buffer to obtain a 25% w / v solution. The two solutions are mixed, forming a hydrogel within 2 seconds. This mixing is performed on biological or artificial tissues or surfaces, where the hydrogel will adhere firmly to them.

[0159] Example 4: Hydrogel synthesis using poloxamer 407 45% oxidized dextran is reacted with poloxamer 407 modified with ethylenediamine. The oxidized dextran is dissolved in water or a biocompatible aqueous buffer to obtain a 10% w / v solution. NH2-poloxamer-407-NH2 is dissolved in water or a biocompatible aqueous buffer to obtain a 20% w / v solution. The two solutions are mixed, forming a hydrogel within 40 seconds. When this mixing is performed on biological or artificial tissues or surfaces, the hydrogel will adhere firmly to them.

[0160] Example 5: Thermal stability of hydrogels The amine component of the hydrogel is based on poloxamer, which exhibits thermogelling properties. Although thermogelling is not necessary since rapid and efficient gelling is achieved by crosslinking of oxidized dextran, once the material reaches physiological temperature, the crosslinked poloxamer chains can rearrange, which creates internal interactions capable of dissipating energy and thus enhancing the mechanical properties of the formed hydrogel.

[0161] Table 3 shows several formulations with different poloxamers and CHO / NH2 ratios and their degradation after 24 hours at 37° C. in the presence of excess saline buffer.

[0162] [Table 3]

[0163] Example 6: Gelation mechanism Figure 2 shows the multiple interaction mechanisms of the composition. The amine-modified poloxamer exhibits temperature-responsive properties, micellizing at moderate temperatures and displaying a highly ordered molecular arrangement at higher temperatures. At the same time, oxidized dextran can react with the terminal amines present in the poloxamer, resulting in robust, stable, and temperature-independent gelation.

[0164] Example 7: Adhesion mechanism of adhesive materials The present invention can achieve strong and durable adhesion to biological and artificial tissues through multiple adhesion mechanisms.

[0165] Example 7A: Covalent Adhesion Mechanism Oxidized dextran contains aldehyde groups that react readily with amines present in proteins and other molecules on the tissue surface. The covalent bond formed between the aldehyde and the amine is an imine bond (Figure 3). Although the imine bond provides a strong bond, it is reversible over time, allowing the material to flake off and be removed as the tissue heals. Although this chemical reaction is rapid, it is not instantaneous.

[0166] Example 7B: Ionic Adhesion Mechanism Ionic interactions are a collection of a wide range of molecular interactions that make a significant contribution to the overall adhesion. In this formulation, the amines present in the PluPEI molecule are the major contributors to the ionic interactions. Protonated amines (positively charged) can interact with negatively charged groups on the tissue surface, e.g., carboxylic acids (Figure 4). Amines can also hydrogen bond with functional groups on the tissue surface. Although ionic interactions provide a very fast and "magnet-like" adhesion, they are not strong enough by themselves to keep materials adhered over the long term.

[0167] Example 7C: Mechanical Interlocking Adhesion Mechanism The tissue surface is like a porous matrix that the sprayed liquid polymer can penetrate (at the molecular level). Once gelation occurs, most of the spray interdigitates within the tissue, providing an additional level of mechanical interaction (Figure 5).

[0168] Example 8: Gel time of adhesive material Gel time is an important parameter for certain applications. In certain embodiments, the adhesive material can achieve almost instantaneous gelation without the need for an external trigger such as UV light or heat. This rapid gelation allows for application in complex geometries accessed by minimally invasive techniques or endoscopy, where very precise targeting of specific sites is required to avoid sagging of the adhesive formulation (Figure 6).

[0169] Example 9: Swelling of adhesive materials Swelling is an important property when delivering hydrogel-based solutions into tight spaces. For gastrointestinal applications, this is not a major issue if the hydrogel swells within the appropriate range. Some commercially available hydrogels can swell up to 1000% of their initial weight. However, some swelling (up to 200%) is desirable, as the increased thickness of the hydrogel can better protect the underlying wound. A higher percentage of water in the material often leads to greater biocompatibility. Excessive hydrogel swelling is also associated with a loss of adhesive properties over time.

[0170] Figure 7 shows the analysis of the surface response of hydrogels with solid contents between 5% and 15%, for both oxidized dextran and PluPEI. There is a clear ratio between the components such that swelling is minimal. When oxidized dextran and PluPEI have similar solid contents, the swelling values ​​are limited to the range of 65% to 75%. If necessary, increasing the solid content beyond 14% further reduces the swelling of the material. An excess of molecules from either component can move the polymer network away from its ideal structure, causing excessive swelling and even reduced stability.

[0171] Example 10: Material flexibility of adhesive material Some sprayable materials become brittle or hard after gelation. It is important that the mechanical properties of the hydrogel remain similar to those of the underlying intestinal tissue. It is also important that the material remains flexible, even when applied in thick layers, as spray volumes may vary from practitioner to practitioner.

[0172] In Figure 8A a thin layer of material, and in Figure 8B a thick layer of material, was bent through 180° without any cracking or breaking of the material. This test was performed 30 minutes after spraying of the material in order to account for its "complete", potentially harder and more brittle, mechanical properties.

[0173] Example 11: Burst pressure of materials in porcine colon tissue Most of the commercially available materials lose their adhesive power when incubated in a physiological environment. For long-term protection and sealing, it is important that the adhesive power of the material is maintained over a long period of time. In Figure 9, it was observed that two formulations of oxidized dextran and PluPEI exhibited superior burst pressures about 10 minutes after spraying compared to several hydrogels containing commercial materials. Furthermore, materials containing various ratios of oxidized dextran (Ox-Dex)-PluPEI were formulations that maintained or showed improved performance when tested after 24 hours of incubation in a physiological environment.

[0174] Example 12: Buffering capacity of hydrogels The high amine concentration found in the PluPEI component gives the hydrogel a strong buffering capacity. Its ability to neutralize acids is evident when the pH of digestive fluids is very high. This is of particular interest in gastric applications where the hydrogels are low and may inhibit the wound healing process. In Figure 10, several hydrogel formulations show a stronger buffering capacity when 0.5 M HCl is added to a PBS solution containing 200 mg of hydrogel compared to PBS alone.

[0175] Example 13: Hydrogel Formulations with Pluronic® Poloxamer 338 and Poloxamer 237 A material with a solids content of 12% PluPEI (poloxamer 338) and 5% oxidized dextran forms a hydrogel in 10 seconds in PBS and swells by approximately 60% after 24 hours. A material with the same concentration of PluPEI (poloxamer 237) forms a hydrogel in 5 seconds in PBS and swells by approximately 45% after 24 hours.

[0176] Example 14: Swelling of Certain Formulations There are several factors that influence the swelling of the resulting hydrogel: by varying the type of poloxamer used in the PluPEI core, the ratio between the components, and the % solids content, a wide range of swelling values ​​can be obtained (Figure 11).

[0177] Example 15: Drug release from hydrogels The high biocompatibility profile and sustained adhesion over time make the oxidized dextran PluPEI hydrogels excellent reservoirs for drug release. Figure 12 shows the in vitro drug release profiles in PBS of the four formulations loaded with 2 mg / mL acriflavine.

[0178] Example 16: Low solids content formulation For applications with less stringent mechanical property requirements or where relatively rapid bioclearance is required, hydrogels with extremely low solids content can be obtained. One low solids content hydrogel was formed by combining 6% PluPEI(407) with 2.5% oxidized dextran (OxDex). This hydrogel had a final total solids content of 4.25% and was stable for 7 days.

[0179] Incorporation by Reference All U.S. and PCT publications and U.S. patents referred to herein are incorporated by reference in their entirety into this application as if each individual publication was specifically and individually indicated to be incorporated by reference. In the case of conflict, the present specification, including specific definitions, will control.

[0180] Other embodiments Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific embodiments described herein. The scope of the embodiments of the invention described herein is not intended to be limited to the above description, but is as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications can be made to the description without departing from the spirit or scope of the invention as defined in the appended claims.

Claims

1. A block copolymer comprising one or more polyethylene oxide (PEO) blocks, one or more polypropylene oxide (PPO) blocks, and at least one primary amine group; and Oxidized polysaccharides containing at least two aldehyde moieties A biocompatible adhesive material including, The adhesive material is crosslinked by a plurality of imine moieties formed from the at least one primary amine of the block copolymer and the at least two aldehyde moieties of the oxidized polysaccharide; the adhesive material is a hydrogel, a biocompatible adhesive material.

2. A functionalized poloxamer represented as FG-PEO-PPO-PEO-FG, wherein each FG independently represents either H or a linker-amine moiety, at least one of the FGs is not H, and each linker-amine moiety independently contains at least one primary amine; and Oxidized polysaccharides containing at least two aldehyde moieties A biocompatible adhesive material including, The adhesive material is crosslinked by a plurality of imine moieties formed from at least one primary amine of the linker-amine moiety of the functionalized poloxamer and one of the aldehyde moieties of the oxidized polysaccharide; the adhesive material is a hydrogel, a biocompatible adhesive material.

3. The molecular weight of the block copolymer or the functionalized poloxamer is approximately 1,000 Da to approximately 25,000 Da, and / or The block copolymer or the functionalized poloxamer is inversely heat sensitive, and / or The block copolymer or the functionalized poloxamer contains 1 to about 50 primary amines. The biocompatible adhesive material according to claim 1 or 2, wherein the PEO block:PPO block ratio of the block copolymer or the functionalized poloxamer is approximately 50:50 to approximately 80:

20.

4. The block copolymer or the functionalized poloxamer is FG-(poloxamer 188)-FG, FG-(poloxamer 237)-FG, FG-(poloxamer 338)-FG, FG-(poloxamer 407)-FG, or any combination thereof, where each FG independently represents H or a primary amine group, and at least one of the FGs is not H, and / or The biocompatible adhesive material according to claim 1 or 2, wherein each of the primary amine groups is independently 1,2-diaminoethane, tris(2-aminoethyl)amine, or a low molecular weight polyethyleneimine having a molecular weight of less than about 2,000 daltons.

5. The molecular weight of the oxidized polysaccharide is approximately 1,000 Da to approximately 100,000 Da, and / or The degree of functionalization of the aforementioned oxidized polysaccharides is approximately 10% to approximately 75%, and / or The biocompatible adhesive material according to claim 1 or 2, wherein the oxidized polysaccharide contains 2 to 100 aldehyde moieties.

6. The biocompatible adhesive material according to claim 1 or 2, wherein the oxidized polysaccharide is dextran.

7. The molecular weight of the dextran is approximately 10 kDa, and / or The biocompatible adhesive material according to claim 6, wherein about 50% of the hydroxyl groups of the dextran are oxidized to aldehydes.

8. A biocompatible adhesive material product for use in methods of treating, bonding, or sealing one or more biological tissues or artificial materials, A first component comprising a block copolymer containing one or more polyethylene oxide (PEO) blocks, one or more polypropylene oxide (PPO) blocks, and at least one primary amine group; and A second component comprising an oxidized polysaccharide containing at least two aldehyde moieties. The method includes, The step of providing the first component; The step of providing the second component; A step of producing an adhesive formulation by combining the first component and the second component; The steps of bringing the adhesive formulation into contact with the surface of one or more biological tissues; and The step of curing the adhesive formulation while it is adhered to the surface of one or more biological tissues. Biocompatible adhesive material products, including [specific material].

9. A biocompatible adhesive material product for use in methods of treating, bonding, or sealing one or more biological tissues or artificial materials, A first component comprising a functionalized poloxamer represented as FG-PEO-PPO-PEO-FG, wherein each FG independently represents either H or a linker-amine moiety, at least one of the FGs is not H, and each linker-amine moiety independently contains at least one primary amine; and A second component comprising an oxidized polysaccharide containing at least two aldehyde moieties. The method includes, The step of providing the first component; The step of providing the second component; A step of producing an adhesive formulation by combining the first component and the second component; The steps of bringing the adhesive formulation into contact with the surface of one or more biological tissues; and The step of curing the adhesive formulation while it is adhered to the surface of one or more biological tissues. Biocompatible adhesive material products, including [specific material].

10. The biocompatible adhesive material product according to claim 8 or 9, further comprising the step of adjusting the concentration of the first component or the second component in order to compensate for the properties of the biological tissue.

11. The molecular weight of the block copolymer or the functionalized poloxamer is approximately 1,000 Da to approximately 25,000 Da, and / or The block copolymer or the functionalized poloxamer is inversely heat sensitive, and / or The block copolymer or the functionalized poloxamer contains 1 to about 50 primary amines, and / or The biocompatible adhesive material product according to claim 8 or 9, wherein the PEO block:PPO block ratio of the block copolymer or the functionalized poloxamer is approximately 50:50 to approximately 80:

20.

12. The block copolymer or the functionalized poloxamer is FG-(poloxamer 188)-FG, FG-(poloxamer 237)-FG, FG-(poloxamer 338)-FG, FG-(poloxamer 407)-FG, or any combination thereof, where each FG independently represents H or a primary amine group, and at least one of the FGs is not H, and / or The biocompatible adhesive material product according to claim 8 or 9, wherein each of the primary amine groups is independently 1,2-diaminoethane, tris(2-aminoethyl)amine, or polyethyleneimine with a low molecular weight of less than about 2,000 daltons.

13. The molecular weight of the oxidized polysaccharide is approximately 1,000 Da to approximately 100,000 Da, and / or The degree of functionalization of the aforementioned oxidized polysaccharides is approximately 10% to approximately 75%, and / or The biocompatible adhesive material product according to claim 8 or 9, wherein the oxidized polysaccharide contains 2 to 100 aldehyde moieties.

14. The biocompatible adhesive material product according to claim 8 or 9, wherein the oxidized polysaccharide is dextran.

15. The molecular weight of the dextran is approximately 10 kDa, and / or The biocompatible adhesive material product according to claim 14, wherein about 50% of the hydroxyl groups of the dextran are oxidized to aldehydes.

16. The biocompatible adhesive material product according to claim 8 or 9, wherein the adhesive formulation is cured while adhered to the surface of one or more biological tissues by covalent bonding, ionic bonding, mechanical bonding, or a combination thereof.

17. The gelation time of the adhesive formulation is approximately 1 second to approximately 100 seconds, and / or The biocompatible adhesive material product according to claim 8 or 9, wherein the swelling value of the adhesive formulation is approximately 30% to approximately 90%.

18. The biocompatible adhesive material product according to claim 8 or 9, wherein the first component and the second component are combined on the surface of one or more biological tissues; the adhesive formulation is formed on the surface of one or more biological tissues; and optionally, the adhesive formulation is formed on a suture line associated with a PTFE or polyester vascular graft.

19. The biocompatible adhesive material product according to claim 8 or 9, wherein the one or more biological tissues are human tissues.

20. The biocompatible adhesive material product according to claim 8 or 9, wherein the first component, the second component, or the first component and the second component further comprises an additive selected from the group consisting of a foaming agent, a pH adjuster, a thickener, an antibacterial agent, a coloring agent, a surfactant, and a radiopaque agent.

21. The biocompatible adhesive material product according to claim 8 or 9, wherein the first component and / or the second component is an aqueous solution.

22. The biocompatible adhesive material product according to claim 8 or 9, wherein the first component, the second component, or the first component and the second component each contain an effective amount of at least one drug.

23. The biocompatible adhesive material product according to claim 22, further comprising the step of diffusing the at least one drug from the adhesive formulation into the biological tissue.

24. The biocompatible adhesive material product according to claim 8 or 9, wherein the adhesive formulation reduces inflammation of the biological tissue, enhances healing, or both.

25. The biocompatible adhesive material product according to claim 8 or 9, wherein the biological tissue is gastrointestinal (GI) tissue.

26. The biocompatible adhesive material product according to claim 8 or 9, wherein the first and second components are provided by an endoscopic technique.

27. A first component comprising a block copolymer containing one or more polyethylene oxide (PEO) blocks, one or more polypropylene oxide (PPO) blocks, and at least one primary amine group; and A second component comprising an oxidized polysaccharide containing at least two aldehyde moieties; The first syringe; and Instructions for use A kit that includes this.

28. A first component comprising a functionalized poloxamer represented as FG-PEO-PPO-PEO-FG, wherein each FG independently represents either H or a linker-amine moiety, at least one of the FGs is not H, and each linker-amine moiety independently contains at least one primary amine; and A second component comprising an oxidized polysaccharide containing at least two aldehyde moieties; The first syringe; and Instructions for use A kit that includes this.

29. The kit according to claim 27 or 28, wherein the first syringe comprises a first reservoir and a second reservoir; the first reservoir contains the first component; the second reservoir contains the second component; and optionally, the first syringe comprises a mixing tip or a spray nozzle.

30. The kit according to claim 27 or 28, further comprising a second syringe, wherein the first component is stored in the first syringe and the second component is stored in the second syringe.

31. The kit according to claim 30, wherein the first syringe and the second syringe each include a mixing tip or a spray nozzle.

32. The kit according to claim 8 or 9, wherein the first component, or the second component, or the first component and the second component, comprises a drug.

33. A drug delivery composition, The biocompatible adhesive material according to claim 1 or 2; and an effective amount of at least one drug Includes, A drug delivery composition wherein at least one drug is mixed with the biocompatible adhesive material.

34. A drug delivery composition according to claim 33, which is brought into contact with biological tissue.

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