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JP-7137213-B2 - Biocompatible adhesives and methods of their use

JP7137213B2JP 7137213 B2JP7137213 B2JP 7137213B2JP-7137213-B2

Inventors

  • リ， ジアンユ
  • セリズ， アダム ディー．
  • ムーニー， デイビッド ジェイ．

Assignees

  • プレジデント アンド フェローズ オブ ハーバード カレッジ
  • プレジデント アンド フェローズ オブ ハーバード カレッジ

Dates

Publication Date
20220914
Application Date
20170322
Priority Date
20160322

Claims (20)

  1. a) a hydrogel comprising a first polymer network and a second polymer network, said first polymer network comprising covalent crosslinks and said second polymer network comprising ionic crosslinks; b) a high density primary amine polymer; and c) a coupling agent, said high density primary amine polymer comprising at least one primary amine per monomer unit and/or chitosan , gelatin, collagen, polyallylamine, polylysine and polyethyleneimine.
  2. The first polymer network comprises polyacrylamide, poly(hydroxyethyl methacrylate) (PHEMA), poly(vinyl alcohol) (PVA), polyethylene glycol (PEG), polyphosphazene, collagen, gelatin, poly(acrylate), poly( methacrylate), poly(methacrylamide), poly(acrylic acid), poly(N-isopropylacrylamide) (PNIPAM), poly(N,N-dimethylacrylamide), poly(allylamine) and copolymers thereof 2. The system of claim 1, selected from:
  3. 3. The system of claim 2, wherein said first polymer network is polyethylene glycol (PEG).
  4. wherein said second polymer network is selected from the group consisting of alginate, pectate, carboxymethylcellulose, oxidized carboxymethylcellulose, hyalnonate, chitosan, κ-carrageenan, ι-carrageenan and λ-carrageenan, said alginate, carboxymethylcellulose, hyalnonate, chitosan; , κ-carrageenan, ι-carrageenan and λ-carrageenan are each optionally oxidized, wherein said alginate, carboxymethylcellulose, hyalnonate, chitosan, κ-carrageenan, ι-carrageenan and λ-carrageenan are methacrylates, acrylates, acrylamides, 4. The system of any one of claims 1-3, optionally comprising one or more groups selected from the group consisting of methacrylamide, thiol, hydrazine, tetrazine, norbornene, transcyclooctene and cyclooctyne. .
  5. 5. The system of claim 4, wherein said second polymer network comprises alginate.
  6. 6. The system of claim 5, wherein said alginate is composed of a mixture of high molecular weight alginate and low molecular weight alginate.
  7. 7. The system of claim 6, wherein the ratio of said high molecular weight alginate to said low molecular weight alginate is from about 5:1 to about 1:5.
  8. 8. The system of any one of claims 1-7, wherein the first polymer network and the second polymer network are covalently linked.
  9. 9. The system of any one of claims 1-8, wherein the hydrogel comprises from about 30% to about 98% water.
  10. 10. The system of any one of claims 1-9, wherein the hydrogel is made in the form of a patch.
  11. 11. The system of any one of claims 1-10, wherein the coupling agent comprises a first carboxyl activating agent.
  12. 12. The system of claim 11, wherein said first carboxyl activating agent is carbodiimide.
  13. 13. The carbodiimide of claim 12, wherein said carbodiimide is selected from the group consisting of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, EDAC or EDCI), dicyclohexylcarbodiimide (DCC) and diisopropylcarbodiimide (DIC). system.
  14. 14. The system of any one of claims 11-13 , wherein the coupling agent further comprises a second carboxyl activating agent.
  15. wherein said second carboxyl activating agent is N-hydroxysuccinimide (NHS), N-hydroxysulfosuccinimide (sulfo-NHS), hydroxybenzotriazole (HOBt), dimethylaminopyridine (DMAP), hydroxy-3,4-dihydro -4-oxo-1,2,3-benzotriazine (HOOBt/HODhbt), 1-hydroxy-7-aza-1H-benzotriazole (HOAt), ethyl 2-cyano-2-(hydroxyimino)acetate, benzotriazole -1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxy-tripyrrolidino-phosphonium hexafluorophosphate, 7-aza-benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluoro phosphate), ethyl cyano(hydroxyimino)acetato-O2)-tri-(1-pyrrolidinyl)-phosphonium hexafluorophosphate, 3-(diethoxy-phosphoryloxy)-1,2,3-benzo[d]triazine-4(3H )-one, 2-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylaminium tetrafluoroborate/hexafluorophosphate, 2-(6-chloro-1H-benzotriazole -1-yl)-N,N,N',N'-tetramethylaminium hexafluorophosphate), N-[(5-chloro-1H-benzotriazol-1-yl)-dimethylamino-morpholino]-uro hexafluorophosphate N-oxide, 2-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylaminium hexafluorophosphate, 1-[1-(cyano -2-ethoxy-2-oxoethylideneaminooxy)-dimethylamino-morpholino]-uronium hexafluorophosphate, 2-(1-oxy-pyridin-2-yl)-1,1,3,3-tetramethylisothio Ouronium tetrafluoroborate, tetramethylfluoroformamidinium hexafluorophosphate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, 2-propanephosphonic anhydride, 4-(4,6-dimethoxy-1 , 3,5-triazin-2-yl)-4-methylmorpholinium salt, (bis-trichloromethyl carbonate 15. The system of claim 14, which is 1,1'-carbonyldiimidazole.
  16. 16. The system of any one of claims 1-15, wherein the high density primary amine polymer and the coupling agent are packaged separately.
  17. 17. The system of any one of claims 1-16, wherein the high density primary amine polymer is in solution and the coupling agent is in solid form.
  18. 18. The system of any one of claims 1-17, wherein the coupling agent is added to a high density primary amine polymer solution.
  19. 19. The system of any one of claims 1-18, wherein the concentration of the high density primary amine polymer in solution is from about 0.1% to about 50%.
  20. said coupling agent comprises at least a first carboxyl activator and optionally a second carboxyl activator, wherein the concentration of said first carboxyl activator in solution is from about 3 mg/mL to about 50 mg /mL.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is filed June 30, 2016, U.S. Provisional Application No. 62/356,939; It claims priority under 311,646. The entire contents of each of these provisional applications are incorporated by reference. GOVERNMENT SUPPORT This invention was made with government support under R01DE0130333 awarded by the National Institutes of Health. The Government has certain rights in this invention. BACKGROUND OF THE INVENTION Tissue adhesives can be used after minimally invasive surgery. However, current tissue adhesive arrays do not meet the requirements in the clinic. For example, current clinically available tissue adhesives such as cyanoacrylates are either toxic or adhere poorly on blood-wetted surfaces, so that under dynamic in vivo environments they Detach easily. The formation of tissue adhesions is often complicated under in vivo conditions due to exposure to fluids (eg, blood) and dynamic tissue movements. An ideal tissue adhesive should (1) adhere strongly to wet biological tissue independently of blood; (2) withstand significant mechanical loads without failure; (3) to prevent unwanted adhesion. (4) must be biocompatible, non-toxic, and have tunable degradation rates; Thus, there is an unmet need for tissue adhesives that exhibit strong adhesion to desired surfaces, particularly wet surfaces of biological tissue, can withstand significant mechanical stress and strain, and are biocompatible. sex is still there. FIG. 1 is a chart (top) comparing the interfacial toughness of a high density primary amine polymer (“crosslinked polymer”, chitosan) in the presence and absence of EDC/NHS (coupling agent) and biocompatible adhesion. Figure 3 is a chart (bottom) showing the increase in interfacial toughness of agents over time. Error bars indicate standard deviation; sample size n=4. FIG. 2(A) is an exemplary biocompatible material of the present invention consisting of a dissipative matrix (light blue area) made of a hydrogel of hybrid ionic and covalent bonds (blue and black lines). 1 is a schematic diagram of an adhesive (tough adhesive, “TA”) and an adhesive surface (light green area) containing high density primary amine polymer with positively charged primary amines (green line). FIG. (B) and (C) are schematics of the proposed adhesion mechanism. (D) Schematic of background hysteresis. (E) is a chart showing the interfacial toughness (adhesion energy) of five representative high density primary amine polymers, including polyallylamine (PAA), chitosan, polyethyleneimine (PEI), collagen and gelatin. Error bars indicate standard deviation; sample size n=4. FIG. 3 shows a first polymer network with covalent crosslinks (top left), a second polymer network with ionic crosslinks (top middle), and an IPN comprising the first and second polymer networks (top right). Schematic; interfacial toughness of first polymer network (PAAM only), second polymer network (alginate only) and IPN (PAAM/alginate) are compared (bottom). Error bars indicate standard deviation; sample size n=4. FIG. 4 is a plot comparing the interfacial toughness of alginate-based IPNs of different molecular weights. Error bars indicate standard deviation. Figure 5 (A) is a schematic showing the sprinkling of blood onto porcine skin prior to the application of TA; (B) is a schematic of the specimen being compressed to allow adhesion to occur. Figures and photographs; (C) is a photograph showing some blood residue remaining at the TA/skin interface after peeling the sample in the 180° peel test; 1 is a schematic of the peel test used to measure the interfacial toughness of the adhesives described in FIG. Figure 6 is a plot of the interfacial toughness of the biocompatible adhesives of the present invention. FIG. 7 is a plot of the interfacial toughness of biocompatible adhesives of the present invention measured in the presence and absence of blood. Figure 8 is a plot of the interfacial toughness of a commercial adhesive cyanoacrylate measured in the presence and absence of blood. Figure 9 is a plot comparing the interfacial toughness of a commercial adhesive cyanoacrylate to the biocompatible adhesive of the present invention. Error bars indicate standard deviation. FIG. 10 shows a series of IPN hydrogels with and without activating agents (chitosan and EDC/sulfo-NHS) immersed in cell culture medium DMEM (left and middle) along with cyanoacrylate (right) for comparison. is a photograph of Cell viability was compared between conditions by quantifying the percentage of viable cells (viability). Scalar bar, 100 μm. Error bars indicate standard deviation; sample size n=5. FIG. 11 is a schematic illustration of cardiac defect formation and closure. Figure 12 is a series of photographs showing a defective heart without (top) and with (middle and bottom) the biocompatible adhesive of the present invention applied. . Figure 13 is a series of photographs showing a device encapsulated in a biocompatible adhesive of th