Powder for achieving hemostasis

Abstract

In various embodiments, the present invention relates to a method of treating or preventing bleeding at a tissue site comprising applying a chitosan powder composition to the tissue site.SOLUTION: In various aspects, the invention relates to a chitosan powder composition for application to a tissue site, the powder composition comprising a chitosan salt, a cross-linked chitosan, a derivatized chitosan, or a combination thereof. In various aspects, the present invention relates to a catheter assembly pre-loaded with a chitosan powder composition and configured to deliver the chitosan powder composition to a tissue site.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a powder for achieving hemostasis. [Background technology]

[0002] Gastrointestinal bleeding affects millions of people each year, and certain cases of internal bleeding cannot be effectively controlled by current hemostatic techniques such as clips, cautery, or band ligation. Summary of the Invention [Problem to be solved by the invention]

[0003] Wounds, surgical sites, diseased tissue, ulcer beds, and gastric varices, among others, are areas where traditional hemostatic measures can fail, leading to prolonged hospitalization or death. [Means for solving the problem]

[0004] In various aspects, the present invention relates to methods of treating or preventing bleeding at a tissue site comprising applying to the tissue site a chitosan powder composition, wherein the chitosan powder composition comprises a chitosan salt, a crosslinked chitosan, a derivatized chitosan, or a combination thereof.

[0005] In various embodiments, the tissue site can be a body cavity, for example, a site within the gastrointestinal tract. If the tissue site is a body cavity, the chitosan powder can be applied, for example, via a catheter or other suitable device.

[0006] In various embodiments that can be used in conjunction with the above aspects and embodiments, the powder can be fluidized in a gas (e.g., CO, nitrogen, air, etc.) to form a fluidized powder that can be sprayed onto the tissue site. In such embodiments, the fluidized powder can be expelled from the catheter at a velocity ranging from 15 to 50 m / s, among other possible velocities.

[0007] In various aspects, the present invention relates to a powder composition for application to a tissue site, the powder composition comprising first particles containing chitosan, a chitosan salt, or a derivatized chitosan, the first particles mixed with second particles containing a crosslinking agent, the crosslinking agent interacting covalently or non-covalently with the first particles upon exposure to moisture.

[0008] In some embodiments, the first particles may include a chitosan salt, and the crosslinker may be a polyanionic crosslinker. For example, the first particles may include chitosan or a chitosan salt, and the crosslinker may be a covalent crosslinker. Examples of covalent crosslinkers include, for example, a multifunctional epoxy, a multifunctional aldehyde, a multifunctional acrylate, genipin, or a derivatized polymer (e.g., an aldehyde-derivatized polymer, an epoxy-derivatized polymer, an acrylate-derivatized polymer, or a genipin-derivatized polymer), among other possibilities.

[0009] In some embodiments that can be used in conjunction with the above aspects and embodiments, the first particle can include a derivatized chitosan and the second particle can include a covalent cross-linking agent. In one particular example, the first particle can include a thiol-modified chitosan and the second particle can include a molecule with multiple unsaturated groups.

[0010] In various aspects, the present invention relates to a powder composition for application to a tissue site comprising a derivatized chitosan. In some embodiments, the derivatized chitosan reacts with cysteine ​​groups in tissue upon exposure to moisture. For example, the derivatized chitosan can be chitosan derivatized with a multifunctional aldehyde, the derivatized chitosan can be chitosan derivatized with a multifunctional epoxide, the derivatized chitosan can be chitosan derivatized with a multifunctional acrylate, or the derivatized chitosan can be chitosan derivatized with genipin.

[0011] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the derivatized chitosan can interact with thiol groups in tissue when exposed to moisture. In some embodiments that may be used in conjunction with the above aspects and embodiments, the derivatized chitosan may be, inter alia, a chitosan derivatized with an unsaturated group, or the derivatized chitosan may be derivatized with a thiol group.

[0012] In various aspects, the present disclosure relates to powder compositions for application to a tissue site comprising a chitosan salt. In some embodiments, the chitosan salt ionically crosslinks with negatively charged species in tissue or blood.

[0013] In various aspects that can be used in conjunction with the above aspects and embodiments, the present invention relates to a catheter assembly that is pre-loaded with a chitosan powder composition and configured to deliver the chitosan powder composition to a tissue site.

[0014] These and other aspects and embodiments are further described in the detailed description that follows. DETAILED DESCRIPTION OF THE INVENTION

[0015] In various aspects, the present invention relates to methods of treating a tissue site (e.g., a wound, a surgical site, a diseased tissue site, an ulcer bed, gastric varices, etc.) to which chitosan powder is applied. The chitosan powder may be applied, for example, to address existing bleeding or to prevent or minimize potential future bleeding. In various embodiments, the tissue site is tissue surrounding a body cavity, e.g., the wall of the gastrointestinal tract. The chitosan powder may include, for example, chitosan, a chitosan salt, cross-linked chitosan, derivatized chitosan, or a natural or synthetic polymer blend comprising the same. As discussed in more detail below, in certain embodiments, the chitosan powder may include, for example, a chitosan salt, cross-linked chitosan, derivatized chitosan, or a combination thereof.

[0016] In various embodiments, chitosan powder may be applied to a tissue site via a catheter. Examples of these include catheter assemblies in which the powder is fluidized in a gas (e.g., compressed air, nitrogen, carbon dioxide, etc.) to form a fluidized powder that is then sprayed onto the tissue site. For example, a catheter assembly may be provided that includes (a) a catheter having a lumen extending therethrough, a proximal end, and a distal end having an exit orifice, and (b) a reservoir containing chitosan powder. The catheter assembly may be configured to deliver the chitosan powder from the reservoir, through the lumen, and out the exit orifice. In certain embodiments, the catheter assembly may have a pressurized reservoir containing pressurized gas for delivering the chitosan powder from the reservoir, through the lumen, and out the exit orifice. For example, the pressurized reservoir may be positioned upstream of the reservoir, and the pressurized gas may pass through the chitosan powder, thereby fluidizing the chitosan powder within the gas and forcing it through the lumen and out the exit orifice. In certain embodiments, the catheter is manipulated so that the fluidized powder exits the catheter at a velocity ranging from 15 m / sec to 50 m / sec.When applied to the gastrointestinal tract, the chitosan powder may be applied through an endoscope.

[0017] In various aspects, the present disclosure relates to a catheter preloaded with chitosan powder. For example, a system may be provided that includes a catheter having a proximal end and a distal end and partially filled with chitosan powder (the remaining volume being air). The catheter may also include seals, such as plugs, caps, or other mechanisms, at the proximal and distal ends of the catheter to retain the chitosan powder. The system may further include a mechanism for applying gas to the catheter at a pressure sufficient to break the proximal seal, fluidize the powder within the catheter, eject the distal seal, and disperse the fluidized chitosan powder from the distal end of the catheter to a treatment site.

[0018] When applied to a tissue site, the chitosan powder of the present invention functions as a barrier to bleeding associated with the tissue site. The chitosan powder functions as a barrier by absorbing liquid, whether it be a bodily fluid such as blood or gastrointestinal fluid (e.g., pancreatic juice, bile, saliva, etc.) present at the tissue site, or a liquid such as saline, phosphate-buffered saline, or contrast fluid applied to the tissue site before, simultaneously with, or after application of the chitosan powder. The chitosan powder can be used to achieve hemostasis at sites of active bleeding or as a prophylactic for clipped areas, suture sites, or other potential bleeding sites, among other uses.

[0019] In various aspects, the present invention relates to chitosan powder that can be used for hemostasis, among other possible uses. Chitosan powders for use in the present invention may be of any suitable particle size. In various embodiments, particle sizes may range, for example, from less than 1 μm to 1000 μm (e.g., 1 μm to 2.5 μm, 10 μm to 25 μm, 50 μm to 100 μm, 250 μm), among other possibilities. In this regard, chitosan powders having particles sized between 50 μm and 425 μm perform well when dispensed through an 8 French catheter.

[0020] As noted above, the chitosan powder can include, for example, chitosan, a chitosan salt, a derivatized chitosan, or a crosslinked chitosan, and optionally a natural or synthetic polymer. Chitosan is a modified polysaccharide containing randomly distributed, β-(1-4)-linked D-glucosamine and N-acetyl-D-glucosamine monomer units. Chitosan is commercially produced by alkaline N-deacetylation of chitin, a cellulose-like polymer composed primarily of unbranched chains of modified glucose, particularly N-acetyl-D-glucosamine.

[0021] The degree of deacetylation in commercially available chitosan is typically in the range of 75-100%, although any degree of deacetylation is possible. Chitosan is positively charged in acidic to neutral solutions, with the charge density depending on the pH and the degree of deacetylation. The pKa value of chitosan generally ranges from 6.1 to 7.0, depending on the degree of deacetylation. Thus, while typically substantially insoluble in distilled water, chitosan is generally soluble in aqueous acidic solutions (e.g., pH about 6.5 or less).

[0022] Examples of chitosan salts include chitosan halides such as chitosan fluoride, chitosan chloride, chitosan bromide, chitosan iodide, chitosan phosphate, chitosan nitrate, chitosan sulfate, chitosan salts of organic monoacids such as formate, acetate, propionate, butyrate, organic diacids such as chitosan salts oxalate, malonate, succinate, maleate, or glutarate, or salts of hydroxy acids such as glycolate, lactate, tartrate, malate, citrate, or gluconate.

[0023] In various embodiments, modified chitosans can be used that exhibit enhanced properties, including improved adhesion. For example, thiol-modified chitosan can be formed by reacting chitosan with a molecule having one or more thiol groups and one or more additional groups (e.g., carboxylic acid groups, also referred to herein as carboxyl groups) for conjugation to the chitosan. In a specific example, the carboxylic acid group of thiolactic acid can react with the primary amine group of chitosan through an appropriate chemical reaction to form a covalent amide bond. For example, carbodiimide conjugation involves activating the carboxylic acid group with a suitable carbodiimide, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), dicyclohexylcarbodiimide (DCC), or N,N'-diisopropylcarbodiimide (DIC), which then allows direct conjugation to primary amines (such as the primary amine groups of chitosan) via amide bond formation. Similarly, carbonyldiimidazole (CDI) can be used in non-aqueous conditions to activate carboxylic acids and directly conjugate them to primary amines (such as the primary amine groups of chitosan) via amide bonds. The thiols of the modified chitosan can interact with cysteine-rich structures to form covalent bonds, enhancing binding.

[0024] Other examples of modified chitosans include chitosans modified with groups that allow for covalent reactions with tissue, including groups that react with amine groups found in tissue. For example, a multifunctional (e.g., bifunctional, trifunctional, etc.) reactive molecule, such as a multifunctional aldehyde molecule, can be reacted with the amine groups on chitosan to form an aldehyde-modified chitosan (i.e., chitosan with pendant aldehyde groups). As another example, a multifunctional (e.g., bifunctional, trifunctional, etc.) reactive molecule, such as a multifunctional epoxide molecule, can be reacted with the amine groups on chitosan to form an epoxy-modified chitosan (i.e., chitosan with pendant epoxide groups). As another example, a multifunctional (e.g., bifunctional, trifunctional, etc.) reactive molecule, such as a multifunctional acrylate molecule, or another molecule having one or more groups that react with chitosan and have at least one acrylate group, such as PEG diacrylate, can react with the thiol groups of thiol-modified chitosan via a Michael-addition click reaction at physiological pH conditions and body temperature to form a chitosan-PEG crosslinked network (i.e., a chitosan-PEG crosslinked gel with an excess of pendant thiol groups that can be modified to covalently bond to tissue). As another example, a multifunctional (e.g., bifunctional, trifunctional, etc.) reactive molecule, such as genipin, can react with amine groups on chitosan to form genipin-modified chitosan (i.e., chitosan with pendant genipin groups). In certain embodiments, the multifunctional reactive molecule (e.g., a multifunctional aldehyde molecule, a multifunctional epoxide molecule, or genipin) can be reacted with chitosan in a relative amount such that the multifunctional reactive molecule is provided at a minimum of 1× mole relative to the number of moles of amine groups on the chitosan, such that all or essentially all of the amine groups are reacted and have pendant reactive groups.

[0025] Examples of polyfunctional aldehydes include glutaraldehyde, glyoxal, and aldehyde-terminated hydrophilic polymers. Examples of polyfunctional epoxides include 4-butanediol diglycidyl ether, ethylene glycol diglycidyl ether, and epoxide-terminated hydrophilic polymers. Hydrophilic polymers with aldehyde or epoxide termini include poly(ethylene glycol) (PEG), poly(ethylene oxide) (PEO), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), polyacrylamide, poly(acrylic acid), and poly(hydroxyethyl methacrylate) (PHEMA). Suitable hydrophilic polymers can range in length from 2 to 250 monomers, among other possibilities.

[0026] In certain embodiments, modified chitosan can be formed by reacting it with a reactive synthetic molecule, such as a PEG diepoxide or a PEG dialdehyde, in a relative amount such that the reactive molecule is provided at a minimum of 1× molar relative to the number of moles of amine groups on the chitosan, such that all or essentially all of the amine groups on the chitosan are reacted and bear pendant epoxide- or aldehyde-terminated PEG groups.

[0027] In some embodiments, chitosan can be directly oxidized, thereby forming aldehyde groups on the chitosan. In some embodiments, chitosan powder may be used in which the chitosan, chitosan salt, modified chitosan, or combinations thereof are non-covalently or covalently crosslinked prior to application to the tissue site or at the time of application to the tissue site.

[0028] For example, in some embodiments, an ionic crosslinker such as a polyfunctional anionic molecule having two or more anionic groups (e.g., carboxylic acid groups or sulfonate groups) can be provided to ionically crosslink chitosan via the positively charged amine groups present on the chitosan. Examples of polyfunctional anionic molecules include salts of organic diacids such as oxalate, malonate, succinate, maleate, or glutarate, or salts of hydroxy acids such as tartrate, malate, or citrate. Examples of polyfunctional anionic molecules also include polyanionic polymers.

[0029] In some embodiments, the polyfunctional anionic molecule is combined and ionically crosslinked with chitosan prior to application to the tissue, and the crosslinked product is ground into a powder, if desired or necessary. In some embodiments, the polyfunctional anionic molecule is ionically crosslinked at the tissue surface. For example, a polyfunctional anionic molecule (e.g., citric acid, among others) may be combined with chitosan in powder form, and the mixture applied to the tissue. When this mixture comes into contact with a moist environment (e.g., provided by bodily fluids and / or a separately applied liquid), the liquid is absorbed, dissolving and crosslinking the powder components, creating a firmer, more cohesive gel with fewer particles throughout the application site.

[0030] In some embodiments, chitosan or modified chitosan may be covalently crosslinked prior to administration and then applied to tissue. For example, chitosan or modified chitosan may be reacted with a multifunctional molecule having two or more groups (e.g., carboxylic acid, amine, epoxy, or aldehyde groups) that react with chitosan (e.g., with the amine groups of chitosan or the carboxymethyl groups of modified chitosan). For example, a biocompatible hydrophilic polymer (e.g., one of the hydrophilic polymers listed above, among others) having terminal carboxylic acid groups can be reacted with the primary amine groups of chitosan by any suitable chemical reaction (e.g., using carbodiimide or carbonyldiimidazole chemistry) to covalently crosslink the chitosan. In one particular embodiment, the carboxylic acid groups of PEG dicarboxylate can be reacted with the amine groups of chitosan using carbodiimide or carbonyldiimidazole chemistry, thereby covalently crosslinking the chitosan. As another example, derivatized chitosan (e.g., chitosan derivatized with carboxylic acid groups) can be crosslinked with a biocompatible hydrophilic polymer (e.g., among others, those listed above) having terminal amine groups through any suitable chemical reaction (e.g., using carbodiimide or carbonyldiimidazole chemistry) to covalently crosslink the chitosan. In one particular embodiment, the amine groups of PEG diamine can be reacted with the carboxylic acid groups of carboxymethylchitosan using carbodiimide or carbonyldiimidazole chemistry, thereby covalently crosslinking the chitosan. The resulting product can be applied to tissue after grinding the product into a powder, if desired or necessary. This generally improves the overall structural integrity of the powder.

[0031] In some embodiments, a chitosan powder is provided that becomes covalently crosslinked upon administration to tissue. For example, first particles containing polyfunctional (e.g., difunctional, trifunctional, etc.) reactive molecules that react with amines, such as genipin, polyfunctional aldehyde molecules, or polyfunctional epoxide molecules (e.g., PEG diepoxide, PEG dialdehyde, or any solid small molecule dialdehyde or small molecule diepoxide) can be mixed with chitosan or chitosan salt powder and applied to tissue in dry form. In certain embodiments, the polyfunctional reactive molecule is a modified chitosan, such as those described above, which can be selected from the aldehyde-modified chitosan (i.e., chitosan with pendant aldehyde groups), epoxy-modified chitosan (i.e., chitosan with pendant genipin groups), and genipin-modified chitosan (i.e., chitosan with pendant genipin groups). When the mixed powder is wetted (e.g., by application of body fluids and / or liquids), the powder components dissolve, and the polyfunctional reactive molecules crosslink with the amines on the chitosan or chitosan salt, further reacting with the amines in the tissue.

[0032] As another example, first particles containing the above-described thiol-modified chitosan can be mixed with second particles containing molecules containing two or more unsaturated groups and applied to tissue in a dry form. Examples of molecules containing two or more unsaturated groups include acrylate-terminated hydrophilic polymers. Hydrophilic polymers that can be provided with unsaturated ends include the hydrophilic polymers described above. A specific example of a molecule containing two or more unsaturated groups is PEG diacrylate. When such a powder is applied to tissue and subsequently mixed in situ with saline, it follows a Michael addition reaction scheme. At body temperature and the pH of saline (7.4), the two powders crosslink to form a cohesive patch. In certain embodiments, the first or second particles may contain a catalyst, such as a base or a nucleophile.

[0033] Various further aspects of the disclosure are provided in the enumerated paragraphs below. Embodiment A1: A method of treating or preventing bleeding at a tissue site, comprising applying chitosan powder to the tissue site, wherein the chitosan powder comprises a chitosan salt, crosslinked chitosan, derivatized chitosan, or a combination thereof.

[0034] Embodiment A2 The method of embodiment A1 is featured, wherein the tissue site is within a body cavity. Embodiment A3 The method of Embodiment A2 is directed to wherein the body cavity is the gastrointestinal tract. Embodiment A4 The method of any one of Embodiments A1 to A3 is summarized as follows: the chitosan powder is applied via a catheter.

[0035] Embodiment A5 The method of any of Embodiments A1-A4, wherein the powder is fluidized in a gas to form a fluidized powder that is sprayed onto the tissue site. Embodiment A6 The method of Embodiment A6 is characterized in that the fluidizing gas is CO2.

[0036] Embodiment A7 The method of any of Embodiments A6-A7 features wherein the fluidized powder exits the catheter at a velocity in the range of 15-50 m / s. Embodiment B1: A pre-filled catheter assembly comprising a catheter having a lumen extending therethrough, a proximal end, and a distal end having an exit orifice, and a reservoir containing chitosan powder, the catheter assembly delivering the chitosan powder from the reservoir through the lumen and out the exit orifice.

[0037] Embodiment B2 The pre-loaded catheter of embodiment B1, wherein the catheter assembly further comprises a pressurized reservoir containing pressurized gas for delivering the chitosan powder from the reservoir, through the lumen, and out the exit orifice.

[0038] Embodiment B3 The pre-loaded catheter of embodiment B2 features a pressurized reservoir disposed upstream of the reservoir, and pressurized gas passes through the chitosan powder, thereby fluidizing the chitosan powder within the gas for delivery through the lumen and out the exit orifice.

[0039] Embodiment B4 The pre-loaded catheter of Embodiment B1, wherein the chitosan powder comprises chitosan, a chitosan salt, a cross-linked chitosan, a derivatized chitosan, or a combination thereof.

[0040] Embodiment C1: The present invention relates to a powder composition for application to a tissue site, the powder composition comprising first particles comprising chitosan, a chitosan salt, or a derivatized chitosan, the first particles being admixed with second particles, the second particles comprising a crosslinker that interacts covalently or non-covalently with the first particles upon exposure to moisture.

[0041] Embodiment C2 The composition of embodiment C1 is characterized in that the first particles comprise a chitosan salt. Embodiment C3 The composition of embodiment C2 is characterized in that the crosslinker is a polyanionic crosslinker.

[0042] Embodiment C4 The composition of embodiment C1 is characterized in that the first particles comprise chitosan or a chitosan salt and the cross-linking agent is a covalent cross-linking agent. Embodiment C5 The composition of Embodiment C4 is characterized in that the covalent crosslinking agent is selected from a multifunctional epoxy, a multifunctional aldehyde, and genipin.

[0043] Embodiment C6 The composition of embodiment C4 is characterized in that the covalent crosslinker is a derivatized polymer. Embodiment C7 The composition of Embodiment C6 is characterized in that the derivatized polymer is selected from an aldehyde-derivatized polymer, an epoxy-derivatized polymer, and a genipin-derivatized polymer.

[0044] Embodiment C8 The composition of Embodiment C6 wherein the derivatized polymer is a derivatized chitosan. Embodiment C9 The composition of Embodiment C8 is characterized in that the derivatized chitosan is selected from aldehyde-derivatized chitosan, epoxy-derivatized chitosan, and genipin-derivatized chitosan.

[0045] Embodiment C10. The composition of embodiment C1 wherein the first particles comprise derivatized chitosan. Embodiment C11 features the composition of embodiment C10, wherein the second particles include a covalent crosslinker.

[0046] Embodiment C12 The composition of Embodiment C11 wherein the covalent crosslinker is a polymeric crosslinker. Embodiment C13 The composition of embodiment C10 is characterized in that the first particles comprise thiol-modified chitosan and the second particles comprise molecules with multiple unsaturated groups.

[0047] Embodiment C14 The composition of embodiment C13 is characterized in that the molecule having multiple unsaturated groups is a hydrophilic polymer having unsaturated end groups. Embodiment D1 The present invention features a powder composition for application to a tissue site, the powder composition including chitosan crosslinked with a multifunctional carboxylated polymer.

[0048] Embodiment D2 The composition of embodiment D1 is characterized in that the carboxylated polymer is a hydrophilic polymer having carboxylic acid end groups. Embodiment D3 The composition of embodiment D1 or D2 wherein the chitosan is crosslinked with the multifunctional carboxylated polymer using diimide coupling.

[0049] Embodiment E1 features a powder composition for application to a tissue site, the powder composition comprising a derivatized chitosan. Embodiment E2 The powder of embodiment E1 wherein the derivatized chitosan reacts with tissue upon exposure to moisture.

[0050] Embodiment E3 The powder of embodiment E1, wherein the derivatized chitosan reacts with primary amine groups in tissue upon exposure to moisture. Embodiment E4 The powder of embodiment E2 wherein the derivatized chitosan is chitosan derivatized with a polyfunctional aldehyde.

[0051] Embodiment E5 The powder of embodiment E2 wherein the derivatized chitosan is chitosan derivatized with a multifunctional epoxide. Embodiment E6 The powder of Embodiment E2, wherein the derivatized chitosan is chitosan derivatized with genipin.

[0052] Embodiment E7 The powder of embodiment E1, wherein the derivatized chitosan interacts with thiol groups in tissue upon exposure to moisture. Embodiment E8 The powder of embodiment E7 wherein the derivatized chitosan is chitosan derivatized with an unsaturated group.

[0053] Embodiment E9 The powder of embodiment E7 wherein the derivatized chitosan is derivatized with a thiol group. Embodiment E10 The powder of embodiment E9 wherein the chitosan is derivatized with a compound containing a carboxylic acid group and a thiol group.

[0054] Embodiment E11 The present invention relates to the powder of embodiment E10, wherein the chitosan is derivatized using diimide (eg, EDC or DCC) coupling. (Example) Chitosan, obtained from Sigma-Aldrich, is suspended in water at a concentration of 2% chitosan and 98% water by weight. The mixture is stirred at room temperature using a mechanical mixer. Acetic acid is then added while stirring until the pH reaches near 5.0 after 5 hours of stirring. 2% citric acid by weight (based on the weight of chitosan initially used) is added to the vessel and mixed for an additional 5 hours. This process forms a gel, which is then dried. The dried gel is then ground into a fine powder for use.

Claims

1. 1. A powder composition for application to a tissue site, the powder composition comprising first particles comprising chitosan, a chitosan salt, or a derivatized chitosan, the first particles being admixed with second particles, the second particles comprising a crosslinking agent that interacts covalently or non-covalently with the first particles upon exposure to moisture.

2. The composition of claim 1 , wherein the first particles comprise a chitosan salt and the crosslinker is a polyanionic crosslinker.

3. The composition of claim 1 , wherein the first particles comprise chitosan or a chitosan salt and the cross-linking agent is a covalent cross-linking agent.

4. The composition of claim 3 , wherein the covalent crosslinking agent is selected from the group consisting of multifunctional epoxies, multifunctional aldehydes, multifunctional acrylates, and genipin.

5. The composition of any one of claims 3 to 4, wherein the covalent cross-linking agent is a derivatized polymer.

6. 6. The composition of claim 5, wherein the derivatized polymer is selected from the group consisting of an aldehyde-derivatized polymer, an epoxy-derivatized polymer, an acrylate-derivatized polymer, and a genipin-derivatized polymer.

7. The composition of claim 1 , wherein the first particles comprise derivatized chitosan.

8. The composition of claim 7 , wherein the second particles comprise a covalent cross-linking agent.

9. The composition of claim 8 , wherein the covalent crosslinker is a polymeric crosslinker.

10. The composition of any one of claims 7 to 9, wherein the first particles comprise thiol-modified chitosan and the second particles comprise molecules with multiple unsaturated groups.

11. A powder composition for application to a tissue site, the powder composition comprising a derivatized chitosan or a chitosan salt.

12. 12. The powder of claim 11, wherein the derivatized chitosan reacts with cysteine ​​groups in tissue upon exposure to moisture or the chitosan salt ionically crosslinks with negatively charged species in tissue or blood.

13. 13. The powder of any one of claims 11 to 12, wherein the derivatized chitosan is chitosan derivatized with a multifunctional aldehyde, or the derivatized chitosan is chitosan derivatized with a multifunctional epoxide, or the derivatized chitosan is chitosan derivatized with genipin.

14. 14. The powder of claim 13, wherein the derivatized chitosan interacts with cysteine ​​in tissue upon exposure to moisture.

15. 15. The powder of claim 14, wherein the derivatized chitosan is a chitosan derivatized with an unsaturated group or the derivatized chitosan is derivatized with a thiol group.