CHITOSAN AND POLYETHYLENE GLYCOL COPOLYMERS AND METHODS AND DEVICES FOR USING SAME FOR SEALING A VASCULAR PUNCTURE
A sealant is provided for sealing a puncture through tissue that comprises an elongate first section including a proximal end, a distal end, and a cross-section sized for delivery into a puncture through tissue, and a second section extending from the distal end of the first section. The first section may be formed from a freeze-dried hydrogel that expands when exposed to physiological fluid within a puncture. The first section comprises chitosan and at least one additional polymer. The second section may be formed from a solid mass of non-freeze-dried, non-cross-linked hydrogel precursors. The precursors are in an unreactive state until exposed to an aqueous physiological environment, whereupon the precursors undergo in-situ crosslinking with one another to provide an adhesive layer bonded to the first section. The second section may further comprise chitosan. Apparatus and methods for delivering the sealant into a puncture through tissue are also provided.
1 . A sealant for sealing a puncture through tissue, comprising:
a first section formed from a freeze-dried hydrogel, wherein the first section expands when exposed to physiological fluid within a puncture; and
wherein the first section comprises a hydrogel comprising chitosan bound to at least one polymer, wherein, upon exposure to an aqueous physiological fluid, the hydrogel expands and seals the puncture through the tissue.
2 . The sealant of claim 1 , wherein the chitosan comprises chitosan that is at least partially deacetylated.
3 . The sealant of claim 2 , wherein the chitosan has a degree of deacetylation of at least 60%.
4 . The sealant of claim 1 , wherein the chitosan has a molecular weight between about 10 kilodaltons and about 600 kilodaltons.
5 . The sealant of claim 1 , wherein the chitosan is selected from the group consisting of free chitosan, chitosan chloride, chitosan glutamate, chitosan acetate, chitosan dicarboxylic acid salts, chitosan adipate, chitosan succinate, chitosan fumarate, and combinations thereof.
6 . The sealant of claim 1 , wherein the at least one polymer comprises one or more of a polyethylene glycol polymer chain with side group functionality.
7 . The sealant of claim 6 , wherein the at least one polymer comprises one or more of an amine modified polyethylene glycol and an ester modified polyethylene glycol.
8 . The sealant of claim 1 , wherein the chitosan is bound to the at least one polymer by a covalent bond.
9 . The sealant of claim 1 , wherein the chitosan is bound to the at least one polymer by a non-covalent bond.
10 . The sealant of claim 1 , wherein the at least one polymer comprises cross-linked polyethylene glycol that is bound to the chitosan.
11 . The sealant of claim 1 , wherein the first section comprises between about 0.1% and about 30% (by weight) chitosan.
12 . The sealant of claim 1 , wherein the at least one polymer comprises polyethylene glycol-amine (PEG-amine) and polyethylene glycol-ester (PEG-ester) and wherein a molar ratio of PEG-amine to PEG-ester is between 4 to 1 and 1 to 4.
13 . The sealant of claim 1 , wherein the at least one polymer comprises polyethylene glycol-amine and polyethylene glycol-ester and wherein an equivalent ratio of active group sites of PEG-amine to PEG-ester is between about 0.1 to about 4.
14 . The sealant of claim 1 , wherein the at least one polymer comprises polyethylene glycol-amine and polyethylene glycol-ester and wherein a molar ratio of chitosan to PEG-ester is between about 0.0005 to about 0.01.
15 . The sealant of claim 1 , wherein the at least one polymer comprises polyethylene glycol-amine and polyethylene glycol-ester and wherein an equivalent ratio of active group sites of chitosan to PEG-ester is between about 0.1 to about 5.
16 . The sealant of claim 1 , wherein the sealant comprises a second section extending from the distal end of the first section.
17 . The sealant of claim 16 , wherein the second section comprises non-cross-linked precursors.
18 . The sealant of claim 17 , wherein the non-crosslinked precursors comprise polyethylene glycol-amine and polyethylene glycol-ester.
19 . The sealant of claim 16 , wherein the second section further comprises chitosan.
20 . The sealant of claim 19 , wherein the second section comprises a mixture of non-cross-linked polyethylene glycols bound to the chitosan.
21 . The sealant of claim 16 , wherein the second section further comprises one or more reinforcement elements with hemostatic properties selected from the group consisting of chitosan reinforcing fibers, chitosan mesh, chitosan particles, or combinations thereof.
22 . The sealant of claim 16 , wherein the second section comprises between about 1% and about 80% (by weight) chitosan.
23 . The sealant of claim 19 , wherein the chitosan is in the form of particles that are incorporated into the second section.
24 . A sealant according to claim 1 , wherein the sealant is configured to seal a vascular puncture, wherein exposure of the sealant to an aqueous physiological fluid causes the sealant to expand, and wherein the sealant has hemostatic and pro-coagulative properties.
25 . The sealant according to claim 16 , wherein the first section has a length between the proximal and distal ends between about 1 and about 20 millimeters, and wherein the second section has a length between about 0.5 and about 5 millimeters.
26 . The sealant according to claim 16 , wherein the first and second sections have a substantially uniform outer cross-section along their lengths between about 1 and about 8 millimeters.
27 . The sealant according to claim 26 , wherein the first and second sections are suitable for expansion in the dimension of the outer cross section of the sealant of at least 50%.
28 - 35 . (canceled)
36 . A method of making a sealant for sealing a puncture through tissue, the method comprising:
forming an elongate first section including a proximal end, a distal end, and a cross-section sized for delivery into a puncture through tissue, the first section formed from a freeze-dried hydrogel comprising polyethylene glycol (PEG) and chitosan, the hydrogel capable of expanding when exposed to a physiological fluid within the puncture; and
applying a second section to the distal end of the first section, the second section comprising a plurality of non-crosslinked PEG precursors, the precursors remaining in an unreactive state until exposed to the physiological fluid within the puncture, whereupon the precursors undergo in-situ crosslinking with one another and to bond to the second section.
37 - 41 . (canceled)
42 . The sealant of claim 1 , wherein the sealant is provided in a device having a diameter that is smaller than a diameter of the puncture.
43 . The sealant of claim 1 , wherein the first section consists essentially of chitosan bound to at least one polymer.
44 . The sealant of claim 1 , wherein the first section further comprises a pH adjusting agent.
45 . The sealant of claim 16 , wherein the second section does not include chitosan.
46 . The sealant of claim 16 , wherein the second section consists essentially of the plurality of non-cross-linked precursors.