Biocompatible adhesive materials and methods of use thereof

Abstract

Biocompatible adhesive materials, such as biocompatible adhesive materials for use with biological tissue and / or medical implants, as well as methods and kits for making and using the biocompatible adhesive materials are provided. The biocompatible adhesive material includes a functionalized poloxamer component and an oxidized polysaccharide component, and can be tailored according to specific tissue types and conditions.

Description

[0001] Related Applications

[0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 336,528, filed on April 29, 2022. Background Art

[0003] Many tissue adhesives have been used in a variety of medical procedures and applications, including local wound closure, supplementing or replacing surgical sutures or staples, bonding synthetic materials to biological tissues, and drug delivery. However, many known tissue adhesives are unsuitable for many applications, for example due to toxic degradation products, slow curing, poor mechanical strength, and other disadvantages.

[0004] A variety of hydrogel adhesives have been developed that are non-toxic and have improved properties. These hydrogels are typically formed by reacting a component having nucleophilic groups with a component having electrophilic groups to form a crosslinked network. However, these hydrogels typically dissolve too quickly, lack sufficient adhesion, or have insufficient mechanical strength.

[0005]

[0006] Therefore, there is a need to provide improved adhesive formulations that overcome one or more of the above-mentioned disadvantages. Summary of the invention

[0006] Biocompatible adhesive materials designed for sealing, coating, bonding or protecting biological and prosthetic materials are disclosed.

[0007] In one aspect, a biocompatible adhesive material is disclosed, comprising:

[0008] 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

[0009] an oxidized polysaccharide comprising at least two aldehyde moieties;

[0010] wherein the binder material is cross-linked via 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; and the binder material is a hydrogel.

[0011] In one aspect, a biocompatible adhesive material is disclosed, comprising:

[0012] A functionalized poloxamer represented by FG-PEO-PPO-PEO-FG, wherein FG at each occurrence independently represents H or a linker-amine moiety, at least one occurrence of FG is not H, and the linker-amine moiety at each occurrence independently comprises at least one primary amine; and

[0013] an oxidized polysaccharide comprising at least two aldehyde moieties;

[0014] wherein the adhesive material is cross-linked through a plurality of imine moieties formed from at least one primary amine of a linker-amine moiety of the functionalized poloxamer and an aldehyde moiety of the oxidized polysaccharide; and the adhesive material is a hydrogel.

[0015] In one aspect, a method of treating, adhering or sealing one or more biological tissues or prosthetic materials is disclosed, the method comprising:

[0016] 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;

[0017] providing a second component comprising an oxidized polysaccharide comprising at least two aldehyde moieties;

[0018] mixing the first component and the second component to produce an adhesive formulation;

[0019] contacting the adhesive formulation with a surface of one or more biological tissues; and

[0020] The adhesive formulation is cured in contact with the surface of one or more biological tissues.

[0021] In one aspect, a method of treating, adhering or sealing one or more biological tissues or prosthetic materials is disclosed, the method comprising:

[0022] providing a first component comprising a functionalized poloxamer represented by FG-PEO-PPO-PEO-FG, wherein FG at each occurrence independently represents H or a linker-amine moiety, at least one occurrence of FG is not H, and the linker-amine moiety at each occurrence independently comprises at least one primary amine;

[0023] providing a second component comprising an oxidized polysaccharide comprising at least two aldehyde moieties;

[0024] mixing the first component and the second component to produce an adhesive formulation;

[0025] contacting the adhesive formulation with a surface of one or more biological tissues; and

[0026] The adhesive formulation is cured in contact with the surface of one or more biological tissues.

[0027] In one aspect, a kit is disclosed, comprising:

[0028] 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

[0029] a second component comprising an oxidized polysaccharide containing at least two aldehyde moieties;

[0030] first syringe; and

[0031] Instructions for use.

[0032] In one aspect, a kit is disclosed, comprising:

[0033] A first component comprising a functionalized poloxamer represented by FG-PEO-PPO-PEO-FG, wherein FG at each occurrence independently represents H or a linker-amine moiety, at least one occurrence of FG is not H, and the linker-amine moiety at each occurrence independently comprises at least one primary amine; and

[0034] a second component comprising an oxidized polysaccharide containing at least two aldehyde moieties;

[0035] first syringe; and

[0036] Instructions for use.

[0037] In one aspect, a drug delivery composition is disclosed, comprising:

[0038] The biocompatible adhesive materials disclosed herein; and

[0039] an effective amount of at least one drug;

[0040] At least one of the drugs is mixed with a biocompatible adhesive material. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] The novel features of the present invention are set forth in detail in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by referring to the following detailed description and accompanying drawings (also referred to herein as "figures") set forth in illustrative embodiments utilizing the principles of the present invention, wherein:

[0042] Figure 1 Figure 2 is a diagram showing the strategy for constructing a family of modified poloxamers.

[0043] Figure 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.

[0044] Figure 3 A diagram of covalent bonding interactions is shown.

[0045] Figure 4 A diagram of the ionic interactions is shown.

[0046] Figure 5 A diagram showing the mechanical interlock.

[0047] Figure 6 Shown is a surface response model of gelation time using different concentrations of oxidized dextran and PEI-modified poloxamer-188 (PluPEI).

[0048] Figure 7 Shown is a surface response model of hydrogel swelling when different concentrations of PEI-modified poloxamer 188 (PluPEI) and oxidized dextran are mixed.

[0049] Fig. 8A It showed that thin layers of material could be bent up to 180 degrees without the material cracking or breaking.

[0050] Figure 8B It showed that thick layers of material could be bent up to 180 degrees without the material cracking or breaking.

[0051] Fig. 9 The burst pressures of several dextran-PluPEI hydrogels at t0 and t24 are shown.

[0052] Fig.10 The buffering capacity exhibited by different hydrogel formulations is shown.

[0053] Fig.11 Swelling at 24 hours is shown for a particular formulation.

[0054] Fig.12 In vitro drug release profiles of acriflavine from several hydrogel formulations are shown. DETAILED DESCRIPTION

[0055] Improved biocompatible adhesive materials, compositions and methods have been developed for bonding, sealing or processing one or more biological tissues. Typically, these biocompatible adhesive materials include functionalized poloxamer components and oxidized polysaccharide components. In some embodiments, the adhesive formulation is used as a tissue adhesive, tissue sealant, tissue treatment agent, matrix material, filler, coating or a combination thereof.

[0056] In one aspect, a biocompatible adhesive material is disclosed, comprising:

[0057] 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

[0058] an oxidized polysaccharide comprising at least two aldehyde moieties;

[0059] wherein the binder material is cross-linked via 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; and the binder material is a hydrogel.

[0060] In certain embodiments, the block copolymer has a molecular weight of about 1,000 Da to about 25,000 Da, or about 1,000 Da to about 20,000 Da.

[0061] In certain embodiments, the block copolymers are reverse thermosensitive.

[0062] 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.

[0063] 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.

[0064] 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, wherein each occurrence of FG independently represents H or a primary amine group, and at least one occurrence of FG is not H.

[0065] In certain embodiments, each occurrence of the primary amine group is independently 1,2-diaminoethane, tris(2-aminoethyl)amine, or a low molecular weight (e.g., less than about 2,000, 1,000, 500, or 250 Daltons) polyethyleneimine. For example, the primary amine group is a 1,2-diaminoethane residue, a tris(2-aminoethyl)amine residue, or a combination thereof. In certain embodiments, the primary amine group is provided by modifying the poloxamer with 1,2-diaminoethane, tris(2-aminoethyl)amine, or a combination thereof.

[0066] In one aspect, a biocompatible adhesive material is disclosed, comprising:

[0067] A functionalized poloxamer represented by FG-PEO-PPO-PEO-FG, wherein FG at each occurrence independently represents H or a linker-amine moiety, at least one occurrence of FG is not H, and the linker-amine moiety at each occurrence independently comprises at least one primary amine; and

[0068] an oxidized polysaccharide comprising at least two aldehyde moieties;

[0069] wherein the adhesive material is cross-linked through a plurality of imine moieties formed from at least one primary amine of a linker-amine moiety of the functionalized poloxamer and an aldehyde moiety of the oxidized polysaccharide; and the adhesive material is a hydrogel.

[0070] In certain embodiments, both occurrences of FG represent a linker-amine moiety.

[0071] In certain embodiments, the functionalized poloxamer has a molecular weight of about 1,000 Da to about 25,000 Da, or about 1,000 Da to about 20,000 Da.

[0072] In certain embodiments, the functionalized poloxamer is reverse thermosensitive.

[0073] In certain embodiments, each linker-amine moiety comprises from 1 to about 50 primary amines.

[0074] In certain embodiments, each linker-amine moiety comprises from 1 to about 25 primary amines.

[0075] 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.

[0076] 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.

[0077] In certain embodiments, the amine moiety of the linker-amine moiety is independently 1,2-diaminoethane, tris(2-aminoethyl)amine, or a low molecular weight (e.g., less than about 2,000, 1,000, 500, or 250 Daltons) polyethyleneimine at each occurrence. For example, the amine moiety of the linker-amine moiety is a 1,2-diaminoethane residue, a tris(2-aminoethyl)amine residue, or a combination thereof. In certain embodiments, the amine moiety of the linker-amine moiety is provided by modifying a poloxamer with 1,2-diaminoethane, tris(2-aminoethyl)amine, or a combination thereof.

[0078] In certain embodiments, the oxidized polysaccharide has a molecular weight of about 1,000 Da to about 100,000 Da.

[0079] In certain embodiments, the degree of functionalization of the oxidized polysaccharide is from about 10% to about 75%.

[0080] In certain embodiments, the oxidized polysaccharide comprises from 2 to 100 aldehyde moieties.

[0081] In certain embodiments, the oxidized polysaccharide comprises 40 to 80 aldehyde moieties.

[0082] In certain embodiments, the oxidized polysaccharide comprises 50 to 70 aldehyde moieties.

[0083] In certain embodiments, the oxidized polysaccharide is dextran.

[0084] In certain embodiments, the dextran has a molecular weight of about 10 kDa.

[0085] In certain embodiments, about 50% of the hydroxyl groups of the dextran are oxidized to aldehydes.

[0086] In certain embodiments, the adhesive material has flexibility to bend up to 180 degrees. In certain embodiments, a three centimeter long sample of the adhesive material has flexibility to bend up to 180 degrees.

[0087] In one aspect, a method of treating, adhering or sealing one or more biological tissues or prosthetic materials is disclosed, the method comprising:

[0088] 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;

[0089] providing a second component comprising an oxidized polysaccharide comprising at least two aldehyde moieties;

[0090] mixing the first component and the second component to produce an adhesive formulation;

[0091] contacting the adhesive formulation with a surface of one or more biological tissues; and

[0092] The adhesive formulation is cured in contact with the surface of one or more biological tissues.

[0093] In certain embodiments, the method further comprises the step of adjusting the concentration of the first component or the second component to compensate for the properties of the biological tissue.

[0094] In certain embodiments, the block copolymer of the method has a molecular weight of about 1,000 Da to about 25,000 Da, or about 1,000 to about 20,000 Da.

[0095] In certain embodiments, the block copolymers of the method are reverse thermosensitive.

[0096] In certain embodiments, the block copolymers of the method comprise from 1 to about 50 primary amines.

[0097] In certain embodiments, the block copolymers of the method comprise from 1 to about 25 primary amines.

[0098] In certain embodiments, the block copolymer of the method has a PEO:PPO ratio of about 50:50 to about 80:20.

[0099] In certain embodiments, the block copolymer of the method is FG-(Poloxamer 188)-FG, FG-(Poloxamer 237)-FG, FG-(Poloxamer 338)-FG, FG-(Poloxamer 407)-FG, or any combination thereof, wherein each occurrence of FG independently represents H or a primary amine group, and at least one occurrence of FG is not H.

[0100] In certain embodiments, each occurrence of the primary amine group of the method is independently 1,2-diaminoethane, tris(2-aminoethyl)amine, or a low molecular weight (e.g., less than about 2,000, 1,000, 500, or 250 Daltons) polyethyleneimine. For example, the primary amine group is a 1,2-diaminoethane residue, a tris(2-aminoethyl)amine residue, or a combination thereof. In certain embodiments, the primary amine group is provided by modifying a poloxamer with 1,2-diaminoethane, tris(2-aminoethyl)amine, or a combination thereof.

[0101] In one aspect, a method of treating, adhering or sealing one or more biological tissues or prosthetic materials is disclosed, the method comprising:

[0102] providing a first component comprising a functionalized poloxamer represented by FG-PEO-PPO-PEO-FG, wherein FG at each occurrence independently represents H or a linker-amine moiety, at least one occurrence of FG is not H, and the linker-amine moiety at each occurrence independently comprises at least one primary amine;

[0103] providing a second component comprising an oxidized polysaccharide comprising at least two aldehyde moieties;

[0104] mixing the first component and the second component to produce an adhesive formulation;

[0105] contacting the adhesive formulation with a surface of one or more biological tissues; and

[0106] The adhesive formulation is cured in contact with the surface of one or more biological tissues.

[0107] In certain embodiments, the method further comprises the step of adjusting the concentration of the first component or the second component to compensate for the properties of the biological tissue.

[0108] In certain embodiments, the functionalized poloxamer of the method has a molecular weight of about 1,000 Da to about 25,000 Da, or about 1,000 to about 20,000 Da.

[0109] In certain embodiments, the functionalized poloxamer of the method is reverse thermosensitive.

[0110] In certain embodiments, each linker-amine moiety of the method comprises from 1 to about 50 primary amines.

[0111] In certain embodiments, each linker-amine moiety of the method comprises from 1 to about 25 primary amines.

[0112] In certain embodiments, the functionalized poloxamer of the method has a PEO:PPO ratio of about 50:50 to about 80:20.

[0113] In certain embodiments, the functionalized poloxamer of the method is FG-(Poloxamer 188)-FG, FG-(Poloxamer 237)-FG, FG-(Poloxamer 338)-FG, FG-(Poloxamer 407)-FG, or any combination thereof.

[0114] In certain embodiments, the amine moiety of the linker-amine moiety of the method is independently 1,2-diaminoethane, tris(2-aminoethyl)amine, or a low molecular weight (e.g., less than about 2,000, 1,000, 500, or 250 Daltons) polyethyleneimine at each occurrence. For example, the amine moiety of the linker-amine moiety is a 1,2-diaminoethane residue, a tris(2-aminoethyl)amine residue, or a combination thereof. In certain embodiments, the amine moiety of the linker-amine moiety is provided by modifying a poloxamer with 1,2-diaminoethane, tris(2-aminoethyl)amine, or a combination thereof.

[0115] In certain embodiments, the oxidized polysaccharide of the method has a molecular weight of about 1,000 Da to about 100,000 Da. Unless otherwise indicated, the "molecular weight" of a polysaccharide refers to the number average molecular weight.

[0116] In certain embodiments, the degree of functionalization of the oxidized polysaccharide of the method is from about 10% to about 75%.

[0117] In certain embodiments, the oxidized polysaccharide of the method comprises from 2 to 100 aldehyde moieties.

[0118] In certain embodiments, the oxidized polysaccharide comprises 40 to 80 aldehyde moieties.

[0119] In certain embodiments, the oxidized polysaccharide comprises 50 to 70 aldehyde moieties.

[0120] In certain embodiments, the oxidized polysaccharide of the method is dextran.

[0121] In certain embodiments, the dextran has a molecular weight of about 10 kDa.

[0122] In certain embodiments, about 50% of the hydroxyl groups of the dextran are oxidized to aldehydes.

[0123] In certain embodiments, curing of the adhesive formulation of the method upon contact with one or more biological tissues comprises covalent bonding, ionic bonding, mechanical interlocking, or a combination thereof.

[0124] In certain embodiments, 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. When the material does not flow, it is considered that a gel has been formed.

[0125] In certain embodiments, the adhesive formulation has a gel time of about 40 seconds to about 80 seconds.

[0126] In certain embodiments, the adhesive formulation has a swell value of about 30% to about 90%.The swell value is the increase in material mass due to penetration of the fluid into the void spaces between the polymer chains of the adhesive formulation.

[0127] In certain embodiments, the adhesive formulation has a swelling value of about 40% to about 75%.

[0128] In certain embodiments, the first component and the second component of the method are mixed on the surface of one or more biological tissues; and the adhesive formulation is formed on the surface of one or more biological tissues; optionally wherein the adhesive formulation is formed on a suture associated with a PTFE or polyester vascular graft.

[0129] In certain embodiments, the one or more biological tissues of the method include human tissue.

[0130] In certain embodiments, the first component, the second component, or both, further comprises an additive selected from the group consisting of a foaming agent, a pH adjuster, a thickener, an antimicrobial agent, a colorant, a surfactant, and a radiopaque agent.

[0131] In certain embodiments, the first component is an aqueous solution.

[0132] In certain embodiments, the second component is an aqueous solution.

[0133] In certain embodiments, the first component, the second component, or both components comprise an effective amount of at least one drug.

[0134] In certain embodiments, the method further comprises the step of allowing at least one drug to diffuse from the adhesive formulation into the biological tissue.

[0135] In certain embodiments, the adhesive formulation of the method reduces inflammation, enhances healing, or both in biological tissue.

[0136] In certain embodiments, the biological tissue is gastrointestinal (GI) tissue.

[0137] In certain embodiments, the first component and the second component are provided using endoscopic techniques.

[0138] In one aspect, a kit is disclosed, comprising:

[0139] 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

[0140] a second component comprising an oxidized polysaccharide containing at least two aldehyde moieties;

[0141] first syringe; and

[0142] Instructions for use.

[0143] In one aspect, a kit is disclosed, comprising:

[0144] A first component comprising a functionalized poloxamer represented by FG-PEO-PPO-PEO-FG, wherein FG at each occurrence independently represents H or a linker-amine moiety, at least one occurrence of FG is not H, and the linker-amine moiety at each occurrence independently comprises at least one primary amine; and

[0145] a second component comprising an oxidized polysaccharide containing at least two aldehyde moieties;

[0146] first syringe; and

[0147] Instructions for use.

[0148] In certain embodiments, a first syringe of the kit comprises a first reservoir and a second reservoir; the first reservoir comprises a first component; and the second reservoir comprises a second component; optionally, the first syringe comprises a mixing tip or nozzle.

[0149] In certain embodiments, the kit further comprises a second syringe.

[0150] 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.

[0151] In certain embodiments, each of the first syringe and the second syringe of the kit comprises a mixing tip or nozzle.

[0152] In certain embodiments, the instructions of the kit explain how to select appropriate concentrations of the first component or the second component or both to compensate for the properties of one or more biological tissues.

[0153] In certain embodiments, the first component or the second component, or both, comprises a drug.

[0154] In one aspect, a drug delivery composition is disclosed, comprising:

[0155] The biocompatible adhesive materials disclosed herein; and

[0156] an effective amount of at least one drug;

[0157] At least one of the drugs is mixed with a biocompatible adhesive material

[0158] In certain embodiments, the drug delivery composition is contacted with biological tissue.

[0159] Typically, adhesive materials can be used on any internal or external biological tissue. Biological tissue can be human or other mammalian tissue. Biological tissue can be natural or artificially produced. Biological tissue can be skin, bone, eye, muscle, blood vessel, dura mater or internal organs, such as lung, intestine, heart, liver, etc. Adhesive formulations can be applied to tissue sites of human or other animal patients, such as during surgery or other medical procedures. In one embodiment, adhesive formulations are used to seal anastomosis. In some embodiments, adhesive formulations are used to bond, seal and / or process wounds, injuries or combinations thereof. For example, adhesive formulations can be applied to wounds that are slow to heal or troublesome, such as wounds of diabetic patients.

[0160] Generally, 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 organ, such as lung, intestine, heart, liver, etc.

[0161] Adhesive materials and / or formulations can be applied to tissue sites of human or other animal patients, such as during surgical or other medical procedures. In one embodiment, adhesive materials are used to seal anastomotic stomas. In some embodiments, adhesive formulations are used to bond, seal and / or treat wounds, injuries or combinations thereof. For example, adhesive formulations can be applied to wounds that are slow to heal or troublesome, such as wounds of diabetic patients. In one embodiment, adhesive formulations can be used to fix or help fix medical implants in human or other animal patients, such as orthopedic implants. In some embodiments, adhesive formulations are used to seal and protect injuries in the gastrointestinal tract, such as gastric ulcers or polypectomy lacerations.

[0162] Poloxamer components

[0163] Generally, poloxamers can be prepared using any known method. In one embodiment, poloxamers are prepared by treating a starting poloxamer having end groups comprising at least one hydroxyl group (e.g., Pluronic F-68) 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 comprise at least one amine.

[0164] In certain embodiments, the poloxamer component or the first component is mixed 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 poloxamer component concentration in the poloxamer component solution is about 5% by weight to about 25% by weight. In another embodiment, the poloxamer component concentration in the poloxamer component solution is about 10% by weight to about 20% by weight. In a further embodiment, the poloxamer component concentration in the poloxamer component solution is about 11% by weight to about 15% by weight.

[0165] In some cases, the poloxamer component or poloxamer component solution may further include an additive. Typically, the amount of the additive may vary depending on the application, tissue type, concentration of the poloxamer component solution, type of the poloxamer component, concentration of the oxidized polysaccharide component solution, and / or type of the oxidized polysaccharide component. Examples of suitable additives include, but are not limited to, pH regulators, 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 includes a foaming additive.

[0166] In a specific embodiment, the poloxamer component or poloxamer component solution comprises at least one drug in an effective amount. In such embodiments, the adhesive formulation can be used as a matrix material for controlled release of the drug. The drug can be substantially any drug suitable for local, regional or systemic administration of a certain amount of adhesive formulation applied to one or more tissue sites of the patient. In one embodiment, the drug includes a thrombotic agent. Non-limiting examples of thrombotic 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 still another embodiment, the drug includes an anti-tumor agent. In still other embodiments, the drug is a drug for gene therapy. For example, the drug may include siRNA molecules for combating cancer. Other drugs are contemplated.

[0167] In other specific embodiments, poloxamer component or poloxamer component solution comprises one or more cells.For example, adhesive formulation can be used as matrix material, for delivering cells to the tissue site to which adhesive formulation is applied.In embodiments, cells can include endothelial cells (EC), endothelial progenitor cells (EPC), hematopoietic stem cells or other stem cells.In one embodiment, cells can release factors to treat cardiovascular disease and / or reduce restenosis.Other types of cells are expected.

[0168] Oxidized polysaccharide fraction

[0169] Typically, the oxidized polysaccharide component or second component includes an oxidized polysaccharide having one or more functional groups capable of reacting with one or more functional groups on biological tissue and / or one or more functional groups on the poloxamer component. In these embodiments, at least one polysaccharide can be linear, branched, or have both linear and branched portions in its structure. Typically, at least one polysaccharide can be natural, synthetic or modified--for example, by cross-linking, changing the substituents of the polysaccharide or both. In one embodiment, at least one polysaccharide is plant-based. In another embodiment, at least one polysaccharide is animal-based. In another embodiment, at least one polysaccharide is bacterially derived. In yet another embodiment, at least one polysaccharide is a combination of plant-based polysaccharides, animal-based polysaccharides, or bacterially derived polysaccharides. Non-limiting examples of polysaccharides include, but are not limited to, dextran, chitin, starch, agar, cellulose, hyaluronic acid, or a combination thereof.

[0170] In some embodiments, the oxidized polysaccharide includes one or more functional groups that will react with one or more functional groups on biological tissue and / or one or more functional groups on the poloxamer component. In one embodiment, at least two or more functional groups incorporated into the oxidized polysaccharide structure are aldehydes.

[0171] In certain embodiments, the functionalization degree of the oxidized polysaccharide is adjustable. "Functionalization degree" generally refers to the number or percentage of reactive groups that are replaced or converted into one or more functional groups required on the oxidized polysaccharide. In one embodiment, the functionalization degree is adjusted according to the type of tissue applied by the adhesive, the concentration of the component and / or the type of oxidized polysaccharide or poloxamer used in the adhesive. In one embodiment, the functionalization degree is about 10% to about 75%. In another embodiment, the functionalization degree is about 15% to about 50%. In another embodiment again, the functionalization degree is about 20% to about 30%.

[0172] In some embodiments, the oxidized polysaccharide includes two or more aldehyde functional groups in the desired percentage. Generally, this oxidation can be carried out using any known method. For example, suitable oxidants include, but are not limited to, periodates, hypochlorites, ozone, peroxides, hydroperoxides, persulfates, and percarbonates. In one embodiment, oxidation is carried out using sodium periodate. Generally, different amounts of oxidants can be used to change the degree of functionalization.

[0173] In certain embodiments, the oxidized polysaccharide component or the second component is mixed 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 includes water, PBS, DMEM or any combination thereof.

[0174] Typically, the oxidized polysaccharide component solution can have any suitable concentration of oxidized polysaccharide component. In one embodiment, the concentration of oxidized polysaccharide component in the oxidized polysaccharide component solution is from about 5% to about 40% by weight. In another embodiment, the concentration of 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 oxidized polysaccharide component in the oxidized polysaccharide component solution is from about 5% to about 25% by weight. Typically, the concentration can be customized and / or adjusted according to the specific application, tissue type, and / or the type and concentration of the poloxamer component used.

[0175] 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 include primary or secondary amines. Typically, the amount of the additive varies depending on the application, tissue type, concentration of the oxidized polysaccharide component solution, the type of oxidized polysaccharide component and / or poloxamer component. Examples of suitable additives include, but are not limited to, pH regulators, thickeners, antimicrobial agents, colorants, surfactants, and radiopaque compounds. In other embodiments, the oxidized polysaccharide component solution includes a foaming agent.

[0176] In certain embodiments, the pH adjusting agent is an acidic compound. Examples of acidic pH adjusting agents include, but are not limited to, carboxylic acids, inorganic acids, and sulfonic acids. In other embodiments, the pH adjusting agent is a basic compound. Examples of basic pH adjusting agents include, but are not limited to, hydroxides, alkoxides, other nitrogen-containing compounds other than primary and secondary amines, basic carbonates, and basic phosphates.

[0177] Generally, the thickener may be selected from any known viscosity adjusting compound including, but not limited to, polysaccharides and their derivatives, such as starch or hydroxyethylcellulose.

[0178] Typically, the surfactant can 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.

[0179] In one embodiment, the radiopaque compound is barium sulfate, gold particles, or a combination thereof.

[0180] In a specific embodiment, the oxidized polysaccharide component or the oxidized polysaccharide component solution comprises at least one drug in an effective amount. In such embodiments, the adhesive formulation can be used as a matrix material for controlled release of the drug. The drug can be substantially any drug suitable for local, regional or systemic administration of a certain amount of adhesive formulation applied to one or more tissue sites of the patient. In one embodiment, the drug includes a thrombotic agent. Non-limiting examples of thrombotic 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 still another embodiment, the drug includes an anti-tumor agent. In still other embodiments, the drug is a drug for gene or cell therapy. For example, the drug may include siRNA molecules for combating cancer. Other drugs are contemplated.

[0181] In other specific embodiments, the oxidized polysaccharide component or the oxidized polysaccharide component solution comprises one or more cells. For example, the adhesive formulation can be used as a matrix material for delivering cells to the tissue site to which the adhesive formulation is applied. In embodiments, the cell can include endothelial cells (EC), endothelial progenitor cells (EPC), hematopoietic stem cells or other stem cells. In one embodiment, the cell can release factors to treat cardiovascular disease and / or reduce restenosis. Other types of cells are contemplated.

[0182] Bioactive and pharmaceutically active agents

[0183] In certain embodiments, one or more bioactive agents can be incorporated into the biocompatible adhesive material of the present invention. The activating agent suitable for the composition of the present invention includes growth factors, such as transforming growth factor (TGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), connective tissue activation peptide (CTAP), osteogenic factor and the biologically active analogs, fragments and derivatives of such growth factors. Particularly preferred members of the transforming growth factor (TGF) supergene family are multifunctional regulatory proteins. 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).

[0184] In addition to the above-mentioned bioactive agents, a large number of pharmaceutical agents are known in the art and can be used in the biocompatible adhesive material of the present invention. The term "pharmaceutical agent" includes, but is not limited to, drugs; vitamins; mineral supplements; substances used to treat, prevent, diagnose, cure or alleviate disease or ailment; or substances that affect the structure or function of the body; or prodrugs, which become biologically active or more active after being placed in a predetermined physiological environment.

[0185] Non-limiting examples of broad classes of useful agents include the following therapeutic agent classes: anabolic agents, antacids, antiasthmatic agents, anticholesterol and antilipid agents, anticoagulants, anticonvulsants, antidysenterics, antiemetics, anti-infectives, anti-inflammatory agents, antimanics, antinauseants, antineoplastic agents, antiobesity agents, antipyretics, antispasmodics, antithrombotics, antigout agents, antianginal agents, antihistamines, antitussives, appetite suppressants, biologics, cerebral vasodilators, coronary vasodilators, decongestants, diuretics, diagnostic agents, erythropoietic agents, expectorants, gastrointestinal analgesics, hyperglycemic agents, hypnotics, hypoglycemic agents, ion exchange resins, laxatives, mineral supplements, mucolytics, neuromuscular agents, peripheral vasodilators, psychotherapeutics, sedatives, stimulants, thyroid and antithyroid agents, uterine relaxants, vitamins and prodrugs.

[0186] More specifically, non-limiting examples of useful agents include the following therapeutic agent classes: analgesics, such as nonsteroidal anti-inflammatory drugs, opioid agonists, and salicylates; antihistamines, such as H1 blockers and H2 blockers; anti-infective agents, such as anthelmintics, anti-anaerobic agents, antibiotics, aminoglycoside antibiotics, antifungal antibiotics, cephalosporin antibiotics, macrolide antibiotics, various beta-lactam antibiotics, penicillin antibiotics, quinolone antibiotics, sulfonamide antibiotics, tetracycline antibiotics, antimycobacterials, antituberculosis antimycobacterials, antiprotozoal drugs, antimalarial antiprotozoal drugs, antiviral agents, antiretroviral agents, antiscabies agents, and urinary tract anti-infective agents; anti-tumor agents, such as alkylating agents, nitrogen mustard alkylating agents, nitrosamines, urea alkylating agents, metabolic antagonists, purine metabolic antagonists, pyrimidine metabolic antagonists, hormonal antineoplastic agents, natural antineoplastic agents, antibiotic natural antineoplastic agents, and vinca alkaloid natural antineoplastic agents; autonomic nervous system agents, such as anticholinergics, antimuscarinic anticholinergics, ergot alkaloids, parasympathomimetics, cholinergic agonist parasympathomimetics, cholinesterase inhibitor parasympathomimetics, sympathomimetics, alpha-blocker sympathomimetics, beta-blocker sympathomimetics, sympathomimetics, and adrenergic agonist sympathomimetics; cardiovascular agents, such as antianginal agents, beta-blocker antianginal agents, calcium channel blocker antianginal agents, nitrate antianginal agents, antiarrhythmics, cardiac glycoside antianginal agents Arrhythmics, Class I antiarrhythmics, Class II antiarrhythmics, Class III antiarrhythmics, Class IV antiarrhythmics, antihypertensives, alpha-blocker antihypertensives, angiotensin-converting enzyme inhibitor (ACE inhibitor) antihypertensives, beta-blocker antihypertensives, calcium channel blocker antihypertensives, centrally acting adrenergic antihypertensives, diuretic antihypertensives, peripheral vasodilator antihypertensives, antilipidemics, bile acid sequestrant antilipidemics, HMG-CoA reductase inhibitor antilipidemics, inotropics, cardiac glycoside inotropics, and thrombolytics; skin agents, such as antihistamines, anti-inflammatory agents, corticosteroid anti-inflammatory agents, antipruritic / local anesthetics, topical anti-infectives, antifungal topical Anti-infectives, antiviral topical anti-infectives, and topical anti-neoplastic agents; electrolyte and renal agents, such as acidifiers, alkalizers, diuretics, carbonic anhydrase inhibitor diuretics, loop diuretics, osmotic diuretics, potassium-sparing diuretics, thiazide diuretics, electrolyte exchangers, and uricosurics; enzymes, such as pancreatic enzymes and thrombolytic enzymes; gastrointestinal drugs, such as antidiarrheals, antiemetics, gastrointestinal anti-inflammatory agents, salicylate gastrointestinal anti-inflammatory agents, antacid anti-ulcer agents, gastric acid pump inhibitor anti-ulcer agents, gastric mucosal anti-ulcer agents, H2-blocking anti-ulcer agents, gallstone dissolving agents, digestives, emetics, laxatives and stool softeners, and prokinetics; general anesthetics, such as inhalation anesthetics, halogenated inhalation anesthetics, intravenous anesthetics, barbiturates, intravenous anesthetics, benzodiazepines Intravenous anesthetics and opioid agonists; hematological agents, such as antianemic agents, hematopoietic antianemic agents, coagulants, anticoagulants, hemostatic coagulants, platelet inhibitors coagulants, thrombolytics enzyme coagulants, and blood volume expanders; hormones and hormone modulators, such as abortifacients, adrenal agents, corticosteroid adrenal agents, androgens, antiandrogens, antidiabetic agents, sulfonylurea antidiabetic agents, antihypoglycemic agents, oral contraceptives, progestogen contraceptives, estrogens, fertility agents, oxytocics, parathyroid agents, pituitary hormones, progestins, antithyroid agents, thyroid hormones, and tocolytics; immunobiological agents, such as immunoglobulins leukemia, immunosuppressants, toxoids and vaccines; local anesthetics, such as amide local anesthetics and ester local anesthetics; musculoskeletal agents, such as antigout anti-inflammatory agents, corticosteroid anti-inflammatory agents, gold compound anti-inflammatory agents, immunosuppressive anti-inflammatory agents, nonsteroidal anti-inflammatory drugs (NSAIDs), salicylate anti-inflammatory agents, skeletal muscle relaxants, neuromuscular blocking skeletal muscle relaxants and reverse neuromuscular blocking skeletal muscle relaxants; neurological agents, such as anticonvulsants, barbiturate anticonvulsants, benzodiazepine anticonvulsants, antimigraine agents, antiparkinsonian agents, antivertigo agents, opioid agonists and opioid antagonists; ophthalmic drugs, such as antiglaucoma drugs, beta-blockers antiglaucoma drugs, ophthalmic medications, miotic antiglaucoma medications, mydriatics, adrenergic agonist mydriatics, antimuscarinic mydriatics, ophthalmic anesthetics, ophthalmic anti-infectives, ophthalmic aminoglycoside anti-infectives, ophthalmic macrolide anti-infectives, ophthalmic quinolone anti-infectives, ophthalmic sulfonamide anti-infectives, ophthalmic tetracycline anti-infectives, ophthalmic anti-inflammatory agents, ophthalmic corticosteroid anti-inflammatory agents and ophthalmic non-steroidal anti-inflammatory drugs (NSAIDs); psychotropic drugs, such as antidepressants, heterocyclic antidepressants, monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, antimanics, antipsychotics, phenothiazine antipsychotics Psychiatric drugs, anxiolytics, sedatives and hypnotics, barbiturate sedatives and hypnotics, benzodiazepine anxiolytics, sedatives and hypnotics, and psychostimulants; respiratory system drugs, such as cough suppressants, bronchodilators, adrenergic agonist bronchodilators, antimuscarinic bronchodilators, expectorants, mucolytics, respiratory anti-inflammatory agents, and respiratory corticosteroid anti-inflammatory agents; toxicology drugs, such as antidotes, heavy metal antagonists / chelators, substance abuse agents, substance abuse deterrents, and substance abuse abstinence agents; minerals; and vitamins, such as vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, and vitamin K.

[0187] Preferred classes of useful agents within the above categories include: (1) nonsteroidal anti-inflammatory drug (NSAID) analgesics, such as diclofenac, ibuprofen, ketoprofen and naproxen; (2) opioid agonist analgesics, such as codeine, fentanyl, hydromorphone and morphine; (3) salicylate analgesics, such as aspirin (ASA) (enteric coated ASA); (4) H1-blocking antihistamines, such as clemastine and terfenadine; (5) H2-blocking antihistamines, such as cimetidine, famotidine, nizadine and ranitidine; (6) anti-infectives, such as mupirocin; (7) anti-anaerobic anti-infectives, such as chloramphenicol and clindamycin; (8) anti-fungal antibiotic anti-infectives, such as amphotericin B, clomiphene citrate and phentermine. (10) various β-lactam antibiotics, such as aztreonam and imipenem; (11) penicillin antibiotics, such as nafcillin, oxacillin, penicillin G and penicillin V; (12) quinolone antibiotics, such as ciprofloxacin and norfloxacin; (13) tetracycline antibiotics, such as doxycycline, minocycline and tetracycline; (14) anti-mycobacterial agents with anti-tuberculosis effects, such as isoniazid (INH) and rifampicin; (15) anti-protozoal agents, such as atovaquone and dapsone; (16) anti-malarial anti-protozoal agents, such as chloroquine and pyrimethamine; (17) antiretroviral anti-infectives, such as ritonavir and zidovudine; (18) antiviral anti-infectives, such as acyclovir, ganciclovir, interferon α and rimantadine; (19) alkylating antineoplastic agents, such as carboplatin and cisplatin; (20) nitrosourea alkylating antineoplastic agents, such as carmustine (BCNU); (21) metabolic antagonist antineoplastic agents, such as methotrexate; (22) pyrimidine metabolic antagonist antineoplastic agents, such as fluorouracil (5-FU) and gemcitabine; (23) hormonal antineoplastic agents, such as goserelin, leuprolide and tamoxifen; (24) natural antineoplastic agents, such as aldesleukin, interleukin 2, docetaxel, etoposide (VP-16), interferon α, paclitaxel and tretinoin (ATRA); (25) antibiotic natural antineoplastic drugs, such as bleomycin, actinomycin D, daunorubicin, doxorubicin and mitomycin; (26) vinca alkaloid natural antineoplastic drugs, such as vinblastine and vincristine; (27) autonomic nervous system agents, such as nicotine; (28) anticholinergic autonomic nervous system agents, such as benztropine and trihexyphenidyl; (29) antimuscarinic anticholinergic autonomic nervous system agents, such as atropine and oxybutynin; (30) ergot alkaloid autonomic nervous system agents, such as bromocriptine; (31) cholinergic agonist parasympathomimetic drugs, such as pilocarpine; (32) cholinesterase inhibitor parasympathomimetic drugs, such as pyridostigmine;(33) α-blocking sympathomimetics, such as prazosin; (34) β-blocking sympathomimetics, such as atenolol; (35) adrenergic agonist sympathomimetics, such as salbutamol and dobutamine; (36) cardiovascular drugs, such as aspirin (ASA) (enteric coated ASA); (37) β-blocking antianginal drugs, such as atenolol and propranolol; (38) calcium channel blocking antianginal drugs, such as nitroglycerin and verapamil; (39) nitrate antianginal drugs, such as isosorbide dinitrate (ISDN); (40) cardiac glycoside antiarrhythmic drugs, such as digoxin; (41) class I antiarrhythmic drugs, such as lidocaine, mexiletine, phenytoin, procainamide and quinidine; (42) class II antiarrhythmic drugs (43) Class III antiarrhythmics, such as amiodarone; (44) Class IV antiarrhythmics, such as diltiazem and verapamil; (45) α-blocker antihypertensives, such as prazosin; (46) angiotensin-converting enzyme inhibitor (ACE inhibitor) antihypertensives, such as captopril and enalapril; (47) β-blocker antihypertensives, such as atenolol, metoprolol, naproxenolol 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, furofuranolide (51) peripheral vasodilators such as hydralazine and minoxidil; (52) antilipidemic agents such as cholesterol-lowering drugs and probucol; (53) bile acid sequestrants such as cholestyramine; (54) HMG-CoA reductase inhibitors such as lovastatin and pravastatin; (55) inotropic agents such as amrinone, dobutamine, and dopamine; (56) cardiac glycosides such as digoxin; (57) thrombolytics such as alteplase (TPA), anistreplase, streptokinase, and urokinase; (58) dermatologic agents such as colchicine, isotretinoin, methotrexate, minoxidil, and tretinoin (ATRA); (59) dermatologic agents such as sedatives. (60) antifungal topical anti-infectives, such as amphotericin B, clomiphene citrate, miconazole, and nystatin; (61) antiviral topical anti-infectives, such as acyclovir; (62) topical antineoplastic agents, such as 5-fluorouracil (5-FU); (63) electrolyte and renal agents, such as galactosidase; (64) loop diuretics, such as furosemide; (65) potassium-sparing diuretics, such as triamterene; (66) thiazide diuretics, such as hydrochlorothiazide (HCTZ); (67) uricosuric agents, such as probenecid; (68) enzymes, such as ribonucleases and deoxyribonucleases; (69) thrombolytic enzymes, such as alteplase, anistreplase, streptokinase, and urokinase;(70) Antiemetics, such as prochlorperazine; (71) Salicylate gastrointestinal anti-inflammatory agents, such as sulfasalazine; (72) Gastric acid pump inhibitor anti-ulcer agents, such as omeprazole; (73) H2-blocking anti-ulcer agents, such as cimetidine, famotidine, nizatidine and ranitidine; (74) Digestive agents, such as pancreatic lipase; (75) Gastrointestinal motility agents, such as erythromycin; (76) Opioid agonist intravenous anesthetics, such as fentanyl; (77) Hematopoietic anti-anemic agents, such as erythropoietic factor, 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 modulators, such as bromocriptine; (82) abortifacients, 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) estrogens, such as conjugated estrogens, diethylstilbestrol (DES), estrogens (estradiol, estrone and estrone sulfate piperazine); (87) fertility factors, such as clomiphene, gonadotropins (HCG) and foetuses; (88) parathyroid agents, such as calcitonin; (89) pituitary hormones, such as desmopressin , goserelin, oxytocin and antidiuretic hormone (ADH); (90) progestins, such as medroxyprogesterone, norethisterone 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, IGIV; (94) ammonia 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 preparations, such as azathioprine, cyclophosphamide and methotrexate; (98) musculoskeletal nonsteroidal anti-inflammatory drugs (NSAIDs), such as diclofenac, ibuprofen, ketoprofen, ketorolac and naproxen; (99) skeletal muscle relaxants, such as baclofenac, cyclobenzaprine and diazepam; (100) skeletal muscle relaxants that reverse neuromuscular blockade, 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 agents, such as bromocriptine, levodopa, carbidopa, and thiopergoline; (106) Antivertigo agents, such as meclizine; (107) Opioid agonists, such as codeine, fentanyl, hydromorphone, methadone, and morphine; (108) Opioid antagonists, such as naloxone; (109) β-blocker antiglaucoma agents, such as timolol; (110) Miotic antiglaucoma agents, such as pilocarpine; (111) Ophthalmic aminoglycoside anti-infective agents, such as gentamicin, neomycin, and phenytoin. ophthalmic quinolone anti-infectives, such as ciprofloxacin, norfloxacin and ofloxacin; (113) ophthalmic corticosteroid anti-inflammatory agents, such as dexamethasone and prednisone; (114) ophthalmic nonsteroidal 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, hydroxychloroquine and cyprodiazepine; ; (117) Psychostimulants, such as methylphenidate and pemerin; (118) Cough suppressants, such as codeine; (119) Bronchodilators, such as theophylline; (120) Adrenergic agonist bronchodilators, such as albuterol; (121) Respiratory corticosteroid anti-inflammatory agents, such as dexamethasone; (122) Antidotes, such as flumazenil and naloxone; (123) Heavy metal antagonists / chelators, such as penicillamine; (124) substance abuse deterrents, such as disulfiram, naltrexone, and nicotine; (125) substance abuse cessation 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.

[0188] In addition to the foregoing, the following less commonly used drugs may be used: chlorhexidine; estradiol cypionate in oil; estradiol valerate in oil; flurbiprofen; flurbiprofen sodium; ivermectin; levodopa; nafarelin; and growth hormone. In addition, the following drugs may be used: recombinant beta-glucan; bovine immunoglobulin concentrate; bovine superoxide dismutase; a formulation comprising fluorouracil, epinephrine, and bovine collagen; recombinant hirudin (r-Hir), HIV-1 immunogen; human anti-TAC antibodies; recombinant human growth hormone (r-hGH); recombinant human hemoglobin (r-Hb); recombinant human mecasermin (r-IGF-1); recombinant interferon beta-1a; levograstim (G-CSF); olanzapine; recombinant thyroid stimulating hormone (r-TSH); and topotecan.

[0189] In addition, the following intravenous products may be used: acyclovir sodium; aldesleukin; atenolol; bleomycin sulfate, human calcitonin; salmon calcitonin; carboplatin; carmustine; actinomycin D, daunorubicin hydrochloride; docetaxel; doxorubicin hydrochloride; epoetin alfa; etoposide (VP-16); fluorouracil (5-FU); ganciclovir sodium; gentamicin sulfate; interferon alfa; leuprolide acetate; meperidine hydrochloride; methadone hydrochloride; methotrexate sodium; paclitaxel; ranitidine hydrochloride; vinblastine sulfate; and zidovudine (AZT).

[0190] Further specific examples of useful agents in the above categories include: (a) antineoplastic agents, such as androgen inhibitors, antimetabolites, cytotoxic agents and immunomodulators; (b) antitussives, such as dextromethorphan, dextromethorphan hydrobromide, noscapine, pentoxyverine citrate and chlorphedianol hydrochloride; (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 phenoxyethanol. 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 and alkaline earth metal salts; (g) ion exchange resins, such as cholestyramine; (h) antiarrhythmics, such as N-acetylprocainamide; (i) antipyretics and analgesics, such as acetaminophen, aspirin, and ibuprofen; (j) appetite suppressants, such as phenylpropanolamine hydrochloride or caffeine; (k) expectorants, such as guaifenesin; (l) antacids, such as aluminum hydroxide and hydrochloric acid. (m) biological agents, such as peptides, polypeptides, proteins and amino acids, hormones, interferons or cytokines and other biologically active peptide compounds, such as interleukin 1-18, including mutants 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 factor ( 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 protein 1-7 (BMP1-7), somatostatin, thymosin-α-1, γ-globulin, superoxide dismutase (SOD), complement factors, hGH, tPA, calcitonin, ANF, EPO and insulin; and (n) anti-infective agents, such as antifungal agents, antiviral agents, antibacterial agents and antibiotics.

[0191] Alternatively, the agent may be a radiosensitizer such as metoclopramide, sensamide or neusensamide (manufactured by Oxigene); profiromycin (manufactured by Vion); RSR13 (manufactured by Allos); Thymitaq (manufactured by Agouron), etanidazole or lobenguane (manufactured by Nycomed); gadolinium texaphrin (manufactured by Pharmacyclics); BuDR / Broxine (manufactured by NeoPharm); IPdR (manufactured by Sparta); CR2412 (manufactured by Cell Therapeutic); L1X (manufactured by Terrapin); etc. Preferably, the biologically active substance is selected from peptides, polypeptides, proteins, amino acids, polysaccharides, growth factors, hormones, anti-angiogenic factors, interferons or cytokines, and prodrugs. In particularly preferred embodiments, the biologically active substance is a therapeutic drug or prodrug, most preferably a drug selected from chemotherapeutic agents and other anti-neoplastic agents (such as paclitaxel), antibiotics, antivirals, antifungals, anti-inflammatory agents, and anticoagulants.

[0192] The biologically active substance is used in a therapeutically effective amount. Although the effective amount of the biologically active substance depends on the specific material used, an amount of about 1% to about 65% of the biologically active substance may be desirable. For some biologically active substances, lesser amounts may be used to achieve effective therapeutic levels.

[0193] Adhesive material or adhesive formulation

[0194] Typically, adhesive materials as described herein or adhesive formulations can be formed by mixing oxidized polysaccharide component or oxidized polysaccharide component solution with poloxamer component or poloxamer component solution in any way. In some embodiments, before biological tissue is contacted with adhesive formulation, oxidized polysaccharide component or oxidized polysaccharide component solution is mixed with poloxamer component or poloxamer component solution. In other embodiments, oxidized polysaccharide component or oxidized polysaccharide component solution is mixed with poloxamer component or poloxamer component solution in any order on biological tissue. In further embodiments, oxidized polysaccharide component or oxidized polysaccharide component solution is applied to the first biological tissue, poloxamer component or poloxamer component solution is applied to the second biological tissue, and the first and second biological tissues are contacted. In still further embodiments, oxidized polysaccharide component or oxidized polysaccharide component solution is applied to the first region of biological tissue, poloxamer component or poloxamer component solution is applied to the second region of biological tissue, and the first region and the second region are contacted.

[0195] Typically, adhesive formulations can be applied to one or more biological tissues as adhesives, sealants and / or treatment agents. One or more biological tissues can be diseased or healthy. In one embodiment, adhesive formulations are applied to one or more biological tissues as adhesives. In another embodiment, adhesive formulations are applied to one or more biological tissues as sealants. In a further embodiment, adhesive formulations are applied to one or more biological tissues as treatment agents. In other embodiments, adhesive formulations are applied to one or more biological tissues as adhesives and sealants. In still another embodiment, adhesive formulations are applied to one or more biological tissues as adhesives and treatment agents. In yet another embodiment, adhesive formulations are applied to one or more biological tissues as sealants and treatment agents. In still further embodiments, adhesive formulations are applied to one or more biological tissues as adhesives, sealants and treatment agents.

[0196] As used herein, when an adhesive material or adhesive formulation improves the response of at least one biological tissue to which it is applied, the adhesive material or adhesive formulation is a "treatment agent". In some embodiments, the improved response is to reduce overall inflammation, improve a specific response at the interface of the wound site / tissue and adhesive formulation, enhance healing or a combination thereof. As used herein, the phrase "reduce overall inflammation" refers to an improvement in the histological score reflecting the severity of inflammation. As used herein, the phrase "improve the specific response at the interface of the wound site / tissue and adhesive formulation" refers to an improvement in the histological score reflecting the severity of serosal neutrophils. As used herein, the phrase "enhance healing" refers to an improvement in the histological score reflecting the severity of serosal fibrosis.

[0197] After contacting one or more biological tissues, the adhesive formulation can be allowed to have enough time to solidify or gel. As used herein, when the adhesive formulation is "solidified" or "gelated", 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. It is not desirable to be bound by any particular theory, and it is believed that the adhesive formulation described herein is effective because the oxidized polysaccharide component reacts with the surface of the poloxamer component and 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 amine on the poloxamer component reacts with the high percentage aldehyde on the oxidized polysaccharide component, thereby reducing toxicity and improving the biocompatibility of the adhesive formulation. Generally, the time required for the adhesive formulation to solidify or gel will vary according to a variety of factors, including but not limited to the characteristics 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 characteristics of one or more biological tissues. In embodiments, the adhesive formulation will fully solidify to provide required bonding or sealing soon after component mixing.Gelation or curing time should ensure that the mixture of components can be delivered to the target area in fluid form before becoming too viscous or solidifying, and then once applied to the target area just solidify rapidly thereafter.In one embodiment, gelation or curing time is less than 120 seconds.In another embodiment, gelation or curing time is between 1 to 100 seconds.In a specific embodiment, gelation or curing time is between 3 to 60 seconds.

[0198] Adhesive Formulation Kits

[0199] In another aspect, a kit is provided, comprising a first part comprising an oxidized polysaccharide component or a solution of an oxidized polysaccharide component, and a second part comprising a poloxamer component or a solution of a poloxamer component. The kit may further comprise an applicator or other device, such as a multi-compartment syringe, for storing, mixing and delivering the two parts and / or the resulting adhesive formulation to a tissue site.

[0200] In certain embodiments, the kit includes at least one syringe. In one embodiment, the syringe includes a separate reservoir of an oxidized polysaccharide component solution and a poloxamer component solution. The syringe may also include a mixing head or a nozzle or a delivery conduit, which mixes two solutions when the plunger is pressed. The mixing head may be detachably fixed to the syringe (so that the mixing head can be replaced), and the mixing head may include a static mixer. In some embodiments, the reservoir in the syringe may have different sizes or may hold solutions of different volumes. In other embodiments, the reservoir in the syringe may be the same size or may hold solutions of the same volume. In a further embodiment, a reservoir may include the first part of the above-mentioned foaming composition, and the second reservoir may include the second part of the foaming composition.

[0201] In a further embodiment, one or more reservoirs of the syringe may be removable. In this embodiment, the removable reservoir may be replaced with a reservoir containing a desired concentration of the oxidized polysaccharide component solution or the poloxamer component solution.

[0202] In preferred embodiments, the kit is sterile. For example, the components of the kit can be packaged together, such as in a tray, a pouch, and / or a box. The packaged kit can be sterilized using known techniques, such as electron beam radiation, gamma radiation, ethylene oxide sterilization, or other suitable techniques.

[0203] definition

[0204] Unless otherwise defined herein, the scientific and technical terms used in this application shall have the meanings commonly understood by those of ordinary skill in the art. Generally, the terms used in connection with chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry and their techniques described herein are those well known and commonly used in the art.

[0205] Unless otherwise indicated, the methods and techniques of the present disclosure are generally performed according to conventional methods well known in the art and as described in various general and more specific references cited and discussed throughout the present specification. 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 Edition", WH Freeman & Co., New York (2000); Griffiths et al., "Introduction to Genetic Analysis, 7th Edition", WH Freeman & Co., NY (1999); and Gilbert et al., "Developmental Biology, 6th Edition", Sinauer Associates, Inc., Sunderland, MA (2000).

[0206] Unless otherwise defined herein, chemical terms used herein are used according to conventional usage in the art as exemplified by “The McGraw-Hill Dictionary of Chemical Terms”, Parker S., ed., McGraw-Hill, San Francisco, CA (1985).

[0207] All of the above and any other publications, patents, and published patent applications mentioned in this application are expressly incorporated herein by reference. In case of conflict, the present specification, including its specific definitions, will control.

[0208] 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 instances where the event or circumstance occurs as well as instances where it does not occur. For example, "optionally substituted alkyl" means that the alkyl group may be substituted as well as instances where the alkyl group is not substituted.

[0209] It is understood that one of ordinary skill in the art can select substituents and substitution patterns on the compounds of the invention to produce chemically stable compounds that can be readily synthesized from readily available starting materials by techniques known in the art and those described below. If 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, as long as a stable structure results.

[0210] Unless indicated to the contrary or the context otherwise indicates, articles such as "a", "an", and "the" may mean one or more than one. Claims or descriptions containing "or" between one or more group members are deemed satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process, unless indicated to the contrary or the context otherwise indicates. The invention includes embodiments in which exactly one group member is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one group member or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0211] "Subjects" intended for administration include, but are not limited to, humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young people, middle-aged people, or the elderly)) and / or non-human animals, such as mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, 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.

[0212] "Effective amount" means the amount of a compound that, when administered to a subject to treat or prevent a disease, is sufficient to achieve such treatment or prevention. "Effective amount" may vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. "Therapeutically effective amount" refers to an effective amount for therapeutic treatment.

[0213] "Prevention" or "prophylactic treatment" refers to reducing the risk of acquiring or developing a disease or condition (i.e., causing a subject who has not been exposed to the causative agent prior to onset of the disease or who is otherwise susceptible to the disease to not develop at least one clinical symptom of the disease).

[0214] The term "prophylaxis" is related to "prevention" and refers to measures or procedures whose purpose is to prevent rather than to treat or cure a disease. Non-limiting examples of prophylaxis may include the administration of vaccines; the administration of low molecular weight heparin to hospitalized patients who are at risk of thrombosis due to, for example, limited mobility, and the administration of antimalarial agents (such as chloroquine) prior to travel to geographical areas where malaria is prevalent or the risk of contracting malaria is high.

[0215] In one embodiment, "treating" or "therapeutic treatment" of any disease or condition refers to ameliorating the disease or condition (i.e., inhibiting the disease or reducing the manifestation, extent, or severity of at least one clinical symptom thereof). In yet another embodiment, "treating" refers to improving at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" refers to modulating the disease or condition physically (e.g., stabilizing a discernible symptom), physiologically (e.g., stabilizing a physical parameter), or both. In a further embodiment, "treating" involves slowing the progression of a disease.

[0216] As used herein, the term "bonding" generally refers to attaching two or more biological tissues permanently or temporarily, or two or more regions of biological tissues. As used herein, the term "sealing" generally refers to at least partially covering or at least partially filling one or more sites on one or more biological tissues, such as wounds. 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 improved or enhanced "response" includes inflammation, healing, or both.

[0217] Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemates, or other forms thereof.Methods for determining stereochemistry and separating stereoisomers are well known in the art.

[0218] Those skilled in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring (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 heterocyclic ring can have from one to four heteroatoms, as long as the heteroaromatic ring is chemically feasible and stable.

[0219] Example

[0220] In order to more fully understand the invention described herein, 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 in any way to limit their scope.

[0221] Example 1: Amine-Terminated Poloxamers

[0222] The first component of the present disclosure consists of an aqueous solution of a homodifunctionalized amine-terminated poloxamer. Poloxamers are linear polymers having an ABA (FG-PEO-PPO-PEO-FG) structure, wherein each occurrence of FG independently represents H or a linker-amine moiety, and at least one occurrence of FG is not H. The triblock structure of poloxamers provides thermosensitive properties to this polymer family.

[0223] Poloxamers are functionalized with different amine-containing molecules to provide a family of polymers with varying numbers of amine end groups. Table 1 shows some examples of amines used to modify poloxamers.

[0224] Table 1. Examples of amine-containing molecules used to modify poloxamer polymers.

[0225] Amine molecules Number of amines per molecule 1,2-Diaminoethane 2 Tris(2-aminoethyl)amine 3 Polyethyleneimine (LMW) ～17

[0226]

[0227] Scheme 1: Synthesis of amine-functionalized poloxamers

[0228] As shown in Scheme 1, poloxamers functionalized with different amine-containing molecules were synthesized following the following synthetic procedure:

[0229] 1. Dissolve 16.8 g of Pluronic F-68 (2 mmol) in 50 mL of acetonitrile (ACN)

[0230] 2. 3.25 g (20 mmol) of 1,1′-carbonyldiimidazole (CDI) was dissolved in 40 mL of ACN and added dropwise to the Pluronic F-68 solution under stirring and inert atmosphere. CDI was used to activate the Pluronic hydroxyl groups at room temperature for 2 hours.

[0231] 3. In a round-bottom flask, dissolve 40 g of polyethyleneimine (PEI) in 40 mL of ACN. Slowly (1 mL / min) add the activated Pluronic solution dropwise onto the stirred PEI. Allow it to react overnight at room temperature.

[0232] 4. ACN was evaporated from the reaction mixture (40°C / 90 mBar) and the resulting solid was redissolved in 100 mL of H2O.

[0233] 5. Extensive dialysis was performed against water using Spectra membrane MWCO 3KDa to remove unreacted PEI and CDI salts. After dialysis for 7 days, the purified solution was freeze-dried to obtain the modified homobifunctionalized Plu-68-PEI.

[0234] In order to generate a family of polymers with a broad range of biological and mechanical properties, different types of poloxamers are used. Some examples of poloxamers providing different molecular weights and hydrophilic / hydrophobic ratios are shown in Table 2.

[0235] Table 2. Examples of nomenclature and properties of some poloxamers used to produce adhesive hydrogels.

[0236]

[0237] Linear poloxamer (polyethylene oxide-polypropylene oxide-polyethylene oxide, PEO-PPO-PEO) polymers of various molecular weights and PEO:PPO ratios were end-functionalized with polyamine molecules ( Figure 1 ). Different PEO:PPO ratios and overall molecular weights provide each of these polymers with specific transition temperatures between its different molecular aggregation states.

[0238] Example 2: Cross-linking agent

[0239] Polysaccharides such as dextran are oxidized to generate aldehyde groups along their backbone. The aldehydes present in the oxidized dextran can readily react with the terminal amines of the modified poloxamer if mixed at the appropriate pH. The reaction of the amine-modified pluronic with the oxidized dextran produces a viscous, biodegradable, and biocompatible hydrogel. The aldehydes and amines form a stable but reversible imine bond. The reversibility of this chemical bond makes the material biodegradable and, therefore, implantable internally.

[0240] Aldehyde dextran was obtained by oxidation of 10 kDa dextran using sodium periodate. The amount of sodium periodate was adjusted to achieve a degree of oxidation of about 40-50%.

[0241] Example 3: Hydrogel Synthesis Using Poloxamer 188

[0242] 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 give a 20% w / v solution. PEI-Poloxamer-188-PEI is dissolved in water or a biocompatible aqueous buffer to give a 25% w / v solution. Upon mixing the two solutions, a hydrogel is formed within 2 seconds. If the mixing is done on top of or on the surface of biological or prosthetic tissue, the hydrogel will adhere firmly to it.

[0243] Example 4: Hydrogel Synthesis Using Poloxamer 407

[0244] 45% oxidized dextran is reacted with poloxamer 407 modified with ethylenediamine. The oxidized dextran is dissolved in water or a biocompatible aqueous buffer to give a 10% w / v solution. NH2-Poloxamer-407-NH2 is dissolved in water or a biocompatible aqueous buffer to give a 20% w / v solution. Upon mixing the two solutions, a hydrogel is formed within 40 seconds. If the mixing is done on top of or on the surface of biological or prosthetic tissue, the hydrogel will adhere firmly to it.

[0245] Example 5: Thermal stability of hydrogels

[0246] The amine component of the hydrogel is based on poloxamers that exhibit thermogelation properties. Although thermogelation is not required due to rapid and efficient gelation achieved by oxidative dextran crosslinking, the crosslinked poloxamer chains can still rearrange once the material reaches physiological temperature, creating internal interactions that can dissipate energy and enhance the mechanical properties of the formed hydrogel.

[0247] Table 3 shows some formulations using different poloxamers and CHO / NH2 ratios and their degradation after 24 hours at 37°C in the presence of excess saline buffer.

[0248] Table 3. Thermal degradation of amine-modified poloxamer / oxidized dextran formulations with different CHO / NH2 ratios.

[0249]

[0250]

[0251] Example 6: Mechanism of gelation

[0252] Figure 2 Multiple interaction mechanisms of the composition were shown. Amine-modified poloxamers showed temperature-responsive properties, exhibiting gelation at moderate temperatures and highly ordered molecular arrangements at higher temperatures. Meanwhile, oxidized dextran could react with the terminal amines present in poloxamers to produce strong, stable, and temperature-independent gelation.

[0253] Example 7: Bonding mechanism of adhesive materials

[0254] The present invention is able to achieve strong and sustained adhesion to biological and prosthetic tissues through the use of multiple adhesion mechanisms.

[0255] Example 7A: Covalent bonding mechanism

[0256] Oxidized dextran contains aldehyde groups, which react readily with amines present in proteins and other molecules on the surface of tissues. The covalent bond created between the aldehyde and the amine is an imine bond ( Figure 3 ). The imine bonds provide a strong bond, but they are reversible over time, allowing the material to separate and be eliminated as the tissue heals. This chemical reaction is fast, but not instantaneous.

[0257] Example 7B: Ionic Bonding Mechanism

[0258] Ionic interactions bring together a broad set of molecular interactions that provide a significant contribution to the overall adhesion. In this formulation, the amines present in the PluPEI molecule are the main contributors to ionic interactions. Protonated amines (positively charged) can interact with negatively charged groups (such as carboxylic acids) on the tissue surface ( Figure 4 ). Amines can also create hydrogen bonds with functional groups on the tissue surface. The ionic interactions provide a very rapid "magnet-like" bond; however, alone, they are not strong enough to keep the material bonded over time.

[0259] Example 7C: Mechanical interlocking bonding mechanism

[0260] The tissue surface acts like a porous matrix into which the sprayed liquid polymer can penetrate (at a molecular level). Once gelation occurs, large volumes of the spray will interlock within the tissue, creating additional levels of mechanical interaction ( Figure 5 ).

[0261] Example 8: Gel Time of Adhesive Materials

[0262] Gel time is an important parameter for certain applications. In certain embodiments, the adhesive material is capable of achieving almost instant gelation without the need for an external trigger (such as UV light or heat). This rapid gelation enables application in complex geometries accessible by minimally invasive techniques or endoscopic examinations, where the adhesive formulation needs to be targeted to very specific locations without dripping. Figure 6 ).

[0263] Example 9: Swelling of Binder Materials

[0264] Swelling is an important property when delivering hydrogel-based solutions in confined spaces. For gastrointestinal applications, this is not a big problem if the hydrogel swells within an appropriate range. Some commercial hydrogels can swell up to 1000% of their initial weight. However, a certain degree of swelling (≤200%) is desirable because the hydrogel with increased thickness forms a better shielding of the underlying wound. A higher percentage of water in the material is often associated with a higher degree of biocompatibility. Excessive hydrogel swelling is also associated with the loss of adhesive properties over time.

[0265] Figure 7 Surface response analysis of hydrogels with solid contents ranging from 5% to 15% for both oxidized dextran and PluPEI is shown. There is a clear ratio between the components that provides the least swelling. When the solid contents of both oxidized dextran and PluPEI are similar, the swelling values ​​are limited to the range of 65%-75%. If desired, increasing the solid content to more than 14% will further reduce the swelling of the material. An excess of molecules from either component can deviate the polymer network from its ideal structure and lead to excessive swelling and even reduced stability.

[0266] Example 10: Material Flexibility of Adhesive Materials

[0267] Some sprayable materials become brittle or stiff after gelation. It is important that the mechanical properties of the hydrogel remain similar to those of the underlying intestinal tissue. Additionally, because there can be variability in spray volumes between clinicians, it is critical that the material remain flexible even when applying thick layers.

[0268] Fig. 8A Medium and thin layer materials Figure 8B Medium-thick layers of material were bent up to 180 degrees without cracking or breaking the material. The test was performed 30 minutes after the material was sprayed to account for its "intact" and potentially harder and more brittle mechanical properties.

[0269] Example 11: Burst Pressure of Materials in Porcine Colon Tissue

[0270] Most commercial materials lose their adhesion once incubated in a physiological environment. For long-term protection and sealing, it is critical that the material maintains adhesion over time. Fig. 9 In a comparison of several hydrogels, including commercial materials, it was observed that two formulations of oxidized dextran and PluPEI showed superior burst pressure within about 10 minutes after spraying. In addition, materials containing different oxidized dextran-PluPEI ratios were the formulations that maintained or improved performance when tested after 24 hours of incubation in a physiological environment.

[0271] Example 12: Buffering capacity of hydrogels

[0272] The high amine concentration present in the PluPEI component provides a strong buffering capacity to the hydrogel. The ability to neutralize acids is of particular interest in gastric applications where digestive secretions have a very low pH and may hinder the wound healing process. Fig.10 In Figure 5, several hydrogel formulations showed strong buffering capacity when 0.5 M HCl was added to PBS solution containing 200 mg of hydrogel compared to PBS alone.

[0273] Example 13: Formation of hydrogels using Pluronic Poloxamer 338 and Poloxamer 237

[0274] A material composed of PluPEI (Poloxamer 338) with 12% solid content and 5% oxidized dextran formed a hydrogel in PBS within 10 seconds and showed about 60% swelling after 24 hours. A material with the same concentration but containing PluPEI (Poloxamer 237) formed a hydrogel in PBS within 5 seconds and showed about 45% swelling after 24 hours.

[0275] Example 14: Swelling of a specific formulation

[0276] There are a variety of factors that affect the swelling of the resulting hydrogels. By modifying 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 ( Fig.11 ).

[0277] Example 15: Drug release from hydrogel

[0278] The high biocompatibility profile and maintained adhesion over time make oxidized dextran PluPEI hydrogels a superior reservoir for drug release. Fig.12 In vitro drug release profiles of four formulations loaded with 2 mg / mL acriflavine in PBS are shown.

[0279] Example 16: Low Solids Formulation

[0280] For those applications requiring less demanding mechanical properties or faster bioelimination, hydrogels with very low solids concentrations can be obtained. A low solids hydrogel was formed by mixing 6% PluPEI (407) and 2.5% OxDex. This hydrogel had a final total solids content of 4.25% and showed stability for 7 days.

[0281] Incorporated by Reference

[0282] All U.S. and PCT patent publications and U.S. patents mentioned herein are incorporated by reference in their entirety to the same extent as if each individual patent publication or patent was specifically and individually indicated to be incorporated by reference. In the event of a conflict, the present application, including any definitions herein, will control.

[0283] Other Implementations

[0284] Those skilled in the art will recognize or be able to determine many equivalents to the specific embodiments described herein using no more than routine experimentation. The scope of the present embodiments described herein is not intended to be limited to the foregoing description, but is as described in the appended claims. Those of ordinary skill in the art will recognize that various changes and modifications may be made to this description without departing from the spirit or scope of the present invention as defined in the appended claims.

Claims

1. A biocompatible adhesive material 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; as well as an oxidized polysaccharide comprising at least two aldehyde moieties; wherein the binder material is cross-linked through 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; and the binder material is a hydrogel. 2 . The biocompatible adhesive material of claim 1 , wherein the block copolymer has a molecular weight of about 1,000 Da to about 25,000 Da, or about 1,000 Da to about 20,000 Da.

3. The biocompatible adhesive material according to claim 1 or 2, wherein the block copolymer is reverse thermosensitive.

4. The biocompatible adhesive material of any one of claims 1-3, wherein the block copolymer comprises 1 to about 50 primary amines.

5. The biocompatible adhesive material of any one of claims 1-4, wherein the block copolymer comprises 1 to about 25 primary amines.

6. The biocompatible adhesive material of any one of claims 1-5, wherein the block copolymer has a PEO block:PPO block ratio of about 50:50 to about 80:

20.

7. A biocompatible adhesive material according to any one of claims 1-6, wherein the block copolymer is FG-(Poloxamer 188)-FG, FG-(Poloxamer 237)-FG, FG-(Poloxamer 338)-FG, FG-(Poloxamer 407)-FG, or any combination thereof, wherein each occurrence of FG independently represents H or a primary amine group, and at least one occurrence of FG is not H.

8. The biocompatible adhesive material of any one of claims 1-7, wherein each occurrence of the primary amine group is independently 1,2-diaminoethane, tris(2-aminoethyl)amine, or a low molecular weight (e.g., less than about 2,000, 1,000, 500, or 250 Daltons) polyethyleneimine.

9. A biocompatible adhesive material comprising: a functionalized poloxamer represented by FG-PEO-PPO-PEO-FG, wherein FG at each occurrence independently represents H or a linker-amine moiety, at least one occurrence of FG is not H, and the linker-amine moiety at each occurrence independently comprises at least one primary amine; and an oxidized polysaccharide comprising at least two aldehyde moieties; wherein the adhesive material is cross-linked through a plurality of imine moieties formed by at least one primary amine of a linker-amine moiety of the functionalized poloxamer and an aldehyde moiety of the oxidized polysaccharide; and the adhesive material is a hydrogel.

10. The biocompatible adhesive material of claim 9, wherein both occurrences of FG represent a linker-amine moiety.

11. The biocompatible adhesive material according to claim 9 or 10, wherein the functionalized poloxamer has a molecular weight of about 1,000 Da to about 25,000 Da, or about 1,000 Da to about 20,000 Da.

12. The biocompatible adhesive material according to any one of claims 9 to 11, wherein the functionalized poloxamer is reverse thermosensitive.

13. The biocompatible adhesive material of any one of claims 9-12, wherein each linker-amine moiety comprises 1 to about 50 primary amines.

14. The biocompatible adhesive material of any one of claims 9-13, wherein each linker-amine moiety comprises from 1 to about 25 primary amines.

15. The biocompatible adhesive material of any one of claims 9-14, wherein the functionalized poloxamer has a PEO:PPO ratio of about 50:50 to about 80:

20.

16. The biocompatible adhesive material according to any one of claims 9-15, wherein the functionalized poloxamer is FG-(Poloxamer 188)-FG, FG-(Poloxamer 237)-FG, FG-(Poloxamer 338)-FG, FG-(Poloxamer 407)-FG, or any combination thereof.

17. A biocompatible adhesive material according to any one of claims 9-16, wherein the amine portion of the linker-amine portion is independently 1,2-diaminoethane, tris(2-aminoethyl)amine, or a low molecular weight (e.g., less than about 2,000, 1,000, 500 or 250 Daltons) polyethyleneimine at each occurrence.

18. The biocompatible adhesive material of any one of claims 1-17, wherein the oxidized polysaccharide has a molecular weight of about 1,000 Da to about 100,000 Da.

19. The biocompatible adhesive material of any one of claims 1-18, wherein the degree of functionalization of the oxidized polysaccharide is from about 10% to about 75%.

20. The biocompatible adhesive material of any one of claims 1-19, wherein the oxidized polysaccharide comprises 2 to 100 aldehyde moieties.

21. The biocompatible adhesive material of claim 20, wherein the oxidized polysaccharide comprises 40 to 80 aldehyde moieties.

22. The biocompatible adhesive material of claim 21, wherein the oxidized polysaccharide comprises 50 to 70 aldehyde moieties.

23. The biocompatible adhesive material of any one of claims 1-22, wherein the oxidized polysaccharide is dextran.

24. The biocompatible adhesive material of claim 23, wherein the dextran has a molecular weight of about 10 kDa.

25. The biocompatible adhesive material of claim 23 or 24, wherein about 50% of the hydroxyl groups of the dextran are oxidized to aldehydes.

26. The biocompatible adhesive material of any one of claims 1 to 25, wherein the adhesive material has flexibility to bend up to 180 degrees.

27. A method of treating, adhering or sealing one or more biological tissues or prosthetic materials, 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; mixing the first component and the second component to produce an adhesive formulation; contacting the adhesive formulation with a surface of one or more biological tissues; and The adhesive formulation is cured in contact with the surface of the one or more biological tissues.

28. The method of claim 27, further comprising the step of adjusting the concentration of the first component or the second component to compensate for the properties of the biological tissue.

29. The method of claim 27 or 28, wherein the block copolymer has a molecular weight of about 1,000 Da to about 25,000 Da, or about 1,000 Da to about 20,000 Da.

30. The method of any one of claims 27-29, wherein the block copolymer is reverse thermosensitive.

31. The method of any one of claims 27-29, wherein the block copolymer comprises from 1 to about 50 primary amines.

32. The method of any one of claims 27-29, wherein the block copolymer comprises from 1 to about 25 primary amines.

33. The method of any one of claims 27-32, wherein the block copolymer has a PEO block:PPO block ratio of about 50:50 to about 80:

20.

34. The method of any one of claims 27-33, wherein the block copolymer is FG-(Poloxamer 188)-FG, FG-(Poloxamer 237)-FG, FG-(Poloxamer 338)-FG, FG-(Poloxamer 407)-FG, or any combination thereof, wherein each occurrence of FG independently represents H or a primary amine group, and at least one occurrence of FG is not H.

35. The method of any one of claims 27-34, wherein each occurrence of the primary amine group is independently 1,2-diaminoethane, tris(2-aminoethyl)amine, or a low molecular weight (e.g., less than about 2,000, 1,000, 500, or 250 Daltons) polyethyleneimine.

36. A method of treating, adhering or sealing one or more biological tissues or prosthetic materials, the method comprising: providing a first component comprising a functionalized poloxamer represented by FG-PEO-PPO-PEO-FG, wherein FG at each occurrence independently represents H or a linker-amine moiety, at least one occurrence of FG is not H, and the linker-amine moiety at each occurrence independently comprises at least one primary amine; providing a second component comprising an oxidized polysaccharide comprising at least two aldehyde moieties; mixing the first component and the second component to produce an adhesive formulation; contacting the adhesive formulation with a surface of one or more biological tissues; and The adhesive formulation is cured in contact with the surface of the one or more biological tissues.

37. The method of claim 36, further comprising the step of adjusting the concentration of the first component or the second component to compensate for the properties of the biological tissue.

38. The method of claim 36, wherein the functionalized poloxamer has a molecular weight of about 1,000 Da to about 25,000 Da, or about 1,000 to about 20,000 Da.

39. The method of any one of claims 36 to 38, wherein the functionalized poloxamer is reverse thermosensitive.

40. The method of any one of claims 36 to 39, wherein each linker-amine moiety comprises from 1 to about 50 primary amines.

41. The method of any one of claims 36 to 40, wherein each linker-amine moiety comprises from 1 to about 25 primary amines.

42. The method of any one of claims 36 to 41, wherein the functionalized poloxamer has a PEO:PPO ratio of about 50:50 to about 80:

20.

43. The method of any one of claims 36 to 42, wherein the functionalized poloxamer is FG-(Poloxamer 188)-FG, FG-(Poloxamer 237)-FG, FG-(Poloxamer 338)-FG, FG-(Poloxamer 407)-FG, or any combination thereof.

44. The method of any one of claims 35 to 43, wherein each occurrence of the amine moiety of the linker-amine moiety is independently 1,2-diaminoethane, tris(2-aminoethyl)amine, or a low molecular weight (e.g., less than about 2,000, 1,000, 500, or 250 Daltons) polyethyleneimine.

45. The method of any one of claims 27 to 44, wherein the oxidized polysaccharide has a molecular weight of about 1,000 Da to about 100,000 Da.

46. ​​The method of any one of claims 27 to 45, wherein the degree of functionalization of the oxidized polysaccharide is from about 10% to about 75%.

47. The method of any one of claims 27 to 46, wherein the oxidized polysaccharide comprises 2 to 100 aldehyde moieties.

48. The method of claim 47, wherein the oxidized polysaccharide comprises 40 to 80 aldehyde moieties.

49. The method of claim 48, wherein the oxidized polysaccharide comprises 50 to 70 aldehyde moieties.

50. The method of any one of claims 27 to 49, wherein the oxidized polysaccharide is dextran.

51. The method of claim 50, wherein the dextran has a molecular weight of about 10 kDa.

52. The method of claim 50 or 51, wherein about 50% of the hydroxyl groups of the dextran are oxidized to aldehydes.

53. The method of any one of claims 27 to 52, wherein curing of the adhesive formulation in contact with the one or more biological tissues comprises covalent bonding, ionic bonding, mechanical interlocking, or a combination thereof.

54. The method of any one of claims 27 to 37, wherein the adhesive formulation has a gel time of about 1 second to about 100 seconds.

55. The method of claim 54, wherein the adhesive formulation has a gel time of about 40 seconds to about 80 seconds.

56. The method of any one of claims 27 to 55, wherein the adhesive formulation has a swelling value of about 30% to about 90%.

57. The method of claim 56, wherein the adhesive formulation has a swelling value of about 40% to about 75%.

58. The method of any one of claims 27 to 57, wherein the first component and the second component are mixed on the surface of the one or more biological tissues; and the adhesive formulation is formed on the surface of the one or more biological tissues; Optional wherein the adhesive formulation is formed on a suture associated with a PTFE or polyester vascular graft.

59. The method of any one of claims 27 to 58, wherein the one or more biological tissues comprise human tissue.

60. The method of any one of claims 27 to 59, wherein the first component, the second component, or both, further comprises an additive selected from the group consisting of a foaming agent, a pH adjuster, a thickener, an antimicrobial agent, a colorant, a surfactant, and a radiopaque agent.

61. The method of any one of claims 27 to 60, wherein the first component is an aqueous solution.

62. The method of any one of claims 27 to 61, wherein the second component is an aqueous solution.

63. The method of any one of claims 27 to 62, wherein the first component, the second component, or both components comprise an effective amount of at least one drug.

64. The method of claim 63, further comprising the step of allowing at least one drug to diffuse from the adhesive formulation into the biological tissue.

65. The method of any one of claims 36 to 64, wherein the adhesive formulation reduces inflammation, enhances healing, or both in the biological tissue.

66. The method of any one of claims 36 to 65, wherein the biological tissue is gastrointestinal (GI) tissue.

67. The method of any one of claims 36 to 66, wherein the first component and the second component are provided using endoscopic techniques.

68. A kit comprising: 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 containing at least two aldehyde moieties; first syringe; and Instructions for use.

69. A kit comprising: A first component comprising a functionalized poloxamer represented by FG-PEO-PPO-PEO-FG, wherein FG at each occurrence independently represents H or a linker-amine moiety, at least one occurrence of FG is not H, and the linker-amine moiety at each occurrence independently comprises at least one primary amine; and a second component comprising an oxidized polysaccharide containing at least two aldehyde moieties; first syringe; and Instructions for use.

70. The kit of claim 68 or 69, wherein the first syringe comprises a first reservoir and a second reservoir; the first reservoir comprises the first component; and the second reservoir comprises the second component; optionally, the first syringe comprises a mixing tip or nozzle.

71. The kit of claim 70, further comprising a second syringe.

72. The kit of claim 71, wherein the first component is stored in the first syringe and the second component is stored in the second syringe.

73. The kit of any one of claims 68 to 72, wherein each of the first syringe and the second syringe comprises a mixing tip or nozzle.

74. A kit according to any one of claims 68 to 73, wherein the instructions explain how to select appropriate concentrations of the first component or the second component or both to compensate for the properties of one or more biological tissues.

75. The kit of any one of claims 68-74, wherein the first component or the second component or both comprise a drug.

76. A drug delivery composition comprising: The biocompatible adhesive material according to any one of claims 1-26; and an effective amount of at least one drug; Wherein the at least one drug is mixed with the biocompatible adhesive material.

77. The drug delivery composition of claim 76, wherein the composition is in contact with biological tissue.

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