Compositions Comprising Activated and Functionalized Prepolymers

Abstract

To provide a composition containing an improved commercially realizable activated and functionalized prepolymer, which can be easily applied to a desired site, has biocompatibility, shows strong adhesive force when once cured / cross-linked, and thereby gives improved sealability / adhesion of a texture, and a method for preparing the same.SOLUTION: A composition comprising an activated group and a prepolymer having an activated and functionalized group on a polymer main chain, having a zeta potential in the range of 0-45 mV, wherein the activated and functionalized group is a group obtainable by a reaction between an activated group and a compound containing a charged nitrogen atom or chargeable nitrogen atom.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a composition comprising an activated and functionalized prepolymer, a method for making the composition, a method for curing the composition, a cured composition obtainable by the method for curing the composition, uses of the composition, and a method for using the composition. [Background technology]

[0002] Open-heart surgery typically relies on suture-based closure or attachment of cardiovascular structures. However, this can be technically challenging due to the fragility of diseased or damaged tissue in adults and young infants, resulting in longer operative times and increased risk of bleeding or dehiscence complications, thus potentially worsening outcomes. Furthermore, cardiopulmonary bypass (CPB), which is required for open-heart surgery, has significant adverse effects, including inflammatory responses and potential neurological complications. Catheter-based interventional procedures for the closure of cardiac defects, such as atrial septal defects (ASDs) and ventricular septal defects (VSDs), have recently emerged to attempt to reduce the invasiveness of surgery, but major challenges remain regarding device fixation within the beating heart. Specifically, fixation of catheter-based cardiac septal defect closure devices currently relies on mechanical means of tissue gripping, which can cause damage to vital structures such as heart valves and specialized conductive tissue. Furthermore, the presence of an insufficient tissue rim around the defect can lead to dislodgement of the prosthesis, damaging nearby structures and leaving a residual defect, limiting the use of the device. Therefore, such methods are applicable only to selected patients due to the anatomical location and geometry of the defect.

[0003] A fast-setting, flexible, and conformable tissue adhesive could be used to bond tissue surfaces together or prosthetic devices to tissue without the need for mechanical entrapment or fixation, thereby avoiding tissue compression and erosion. Such materials could potentially have broad applications not only in minimally invasive cardiac repair, but also in soft tissue repair with potentially minimal scarring and damage. For example, in vascular surgery, suture-based anastomoses do not always provide instant hemostasis and can create endothelial irregularities that predispose to thrombosis. Furthermore, the presence of permanent sutures can cause a foreign body reaction at the repair site with additional inflammation and scarring, increasing the risk of delayed vascular occlusion. Tissue adhesives could provide instant sealing and achieve repair with minimal scarring or tissue damage.

[0004] Currently, clinically available adhesives, such as medical-grade cyanoacrylate (CA) or fibrin sealants, exhibit weak adhesive properties that are easily washed off or harden under dynamic, wet conditions, are toxic and therefore unsuitable for use inside the body, and / or cannot withstand the internal forces of cardiac chambers and major blood vessels. Many such adhesives also exhibit activation properties that make device fine-tuning and repositioning extremely difficult. Furthermore, many adhesives under development achieve tissue adhesion only through chemical reactions with functional groups on the tissue surface, rendering them ineffective in the presence of blood. Alternatives to cyanoacrylates have been explored. U.S. Patent No. 8,143,042 describes biodegradable elastomers prepared by crosslinking prepolymers containing crosslinkable functional groups, such as acrylate groups. U.S. Patent No. 8,143,042 also discloses that increasing the number of free hydroxyl groups on the polymer is desirable to enhance the polymer's adhesive properties. Increasing the number of hydroxyl groups in the backbone also increases solubility in physiological solutions. This suggests that the primary mechanism of polymer adhesion is chemical interaction between the functional groups (e.g., free hydroxyl groups on the polymer) and the tissue to which the polymer is applied. However, as shown by Artzi et al., Adv. Mater. 21, 3399-3403 (2009), this type of chemical interaction becomes ineffective in the presence of body fluids, particularly blood.

[0005] Similarly, Mahdavi et al., 2008, PNAS, pp. 2307–2312, described nanopatterned elastomeric polymers and proposed that applying a thin layer of aldehyde-functionalized oxidized dextran (DXTA) increases adhesive strength by promoting covalent crosslinking between the terminal aldehyde groups of DXTA and amine groups on tissue proteins. This adhesive mechanism, which is essentially based on covalent bonding between radicals generated during the curing process and tissue functional groups, has several limitations. The use of adhesives with reactive chemistry requires that the tissue surface be dry before applying the prepolymer, making their use in cardiac applications, such as during first aid, extremely difficult. In addition, reactive chemistry can denature proteins and tissues and promote unwanted immune responses (e.g., local inflammation) that can lead to adhesive rejection. Furthermore, reactive chemistry that only binds to the tissue surface may result in poor adhesion due to a more defined interface, and therefore, there may be a mismatch in mechanical properties at the interface between the adhesive and the tissue. Elastomeric crosslinked polyesters are disclosed in U.S. Patent Application Publication No. 2013 / 0231412. Biodegradable polymers are disclosed in U.S. Patent No. 7,722,894. Adhesive articles are disclosed in WO / 2009 / 067482A1 and WO2014 / 190302A1. Blood-resistant surgical adhesives are described by Lang et al. in "A Blood-Resistant Surgical Glue for Minimally Invasive Repair of Vessels and Heart Defects," Sci. Transl. Med., 8 January 2014: Vol. 6, Issue 218, p. 218ra6 and WO2014 / 190302A1. Summary of the Invention

[0006] The present invention provides improved, commercially viable activated and functionalized prepolymers that can be easily applied to the desired site, are biocompatible (non-toxic), and once cured / crosslinked, exhibit strong adhesive strength, thereby providing improved tissue sealing / adhesion. The improved activated and functionalized prepolymers remain at the desired site before curing / crosslinking, even in the presence of bodily fluids such as blood. When stored, the improved activated and functionalized prepolymers are stable. More specifically, the present invention provides a composition comprising a prepolymer having activated and functionalized groups on the polymer backbone, the composition having a zeta potential in the range of 0 to 45 mV. The present invention also provides a method for preparing the composition of the present invention. The present invention further provides a method of curing the composition of the present invention, the method comprising curing the composition by a stimulus, for example by light in the presence of a photoinitiator. The present invention also provides a cured composition obtainable by the curing method of the present invention, said cured composition being desirably an adhesive, i.e. capable of strongly bonding to a surface or bonding one surface to another. The present invention further provides methods of using the compositions of the present invention and uses of the compositions to adhere or seal tissue or to adhere medical devices to the surface of tissue. The inventors have discovered that the present invention, compared to known compositions, offers advantages not found in the prior art. [Brief explanation of the drawings]

[0007] [Figure 1] FIG. 1 shows a graph comparing the zeta potential of compositions of the present invention with the adhesive strength of the compositions after curing. [Figure 2] FIG. 2 illustrates the synthesis of a composition of the present invention. [Figure 3] FIG. 3 illustrates the synthesis of a composition of the present invention. [Figure 4] FIG. 4 illustrates the synthesis of a composition of the present invention. [Figure 5] FIG. 5 illustrates the synthesis of a composition of the present invention. [Figure 6] FIG. 6 illustrates the synthesis of a composition of the present invention. [Figure 7] FIG. 7 illustrates the synthesis of a composition of the present invention. [Figure 8] FIG. 8 illustrates the synthesis of a composition of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0008] Prepolymer Preferably, the polymer backbone of the prepolymer has the general formula (-AB-) n In the formula, A is derived from a substituted or unsubstituted polyol or a mixture thereof, B is derived from a substituted or unsubstituted polyacid or a mixture thereof, and n is an integer greater than 1. The polymer backbone is composed of repeating monomer units of the general formula -AB-. The term "substituted" has its ordinary meaning in chemical nomenclature and is used to describe compounds in which a hydrogen on the main carbon chain has been replaced with a substituent, e.g., alkyl, aryl, carboxylic acid, ester, amide, amine, urethane, ether, or carbonyl.

[0009] Component A of the prepolymer can be derived from a polyol or a mixture thereof (e.g., diol, triol, tetraol, or higher polyols). Suitable polyols include diols (e.g., alkanediols, preferably octanediol); triols (e.g., glycerol, trimethylolpropane, trimethylolpropane ethoxylate, triethanolamine); tetraols (e.g., erythritol, pentaerythritol); and higher polyols (e.g., sorbitol). Component A can also be derived from unsaturated polyols, such as tetradeca-2,12-diene-1,14-diol, polybutadiene-diol, or other polyols, including macromonomer polyols, such as polyethylene oxide, polycaprolactone triol, and N-methyldiethanolamine (MDEA). Preferably, the polyol is substituted or unsubstituted glycerol. Component B of the prepolymer is derived from a polyacid or mixture thereof, preferably a diacid or triacid. Exemplary acids include, but are not limited to, glutaric acid (5 carbons), adipic acid (6 carbons), pimelic acid (7 carbons), sebacic acid (8 carbons), azelaic acid (9 carbons), and citric acid. Exemplary long-chain diacids include those having more than 10, more than 15, more than 20, and more than 25 carbon atoms. Non-aliphatic diacids may also be used. For example, variants of the above diacids having one or more double bonds can be used to produce polyol-diacid copolymers. Preferably, the polyacid is substituted or unsubstituted sebacic acid.

[0010] The polyol-based polymers described in U.S. Patent Application Publication No. 2011 / 0008277, U.S. Patent No. 7,722,894, and U.S. Patent No. 8,143,042, the contents of which are incorporated herein by reference, are suitable polymer backbones for use in the present invention. Several substituents, such as amines, aldehydes, hydrazides, acrylates, and aromatic groups, can be incorporated into the carbon chain. Exemplary aromatic diacids include terephthalic acid and carboxyphenoxy-propane. The diacids may also contain substituents. For example, reactive groups such as amines and hydroxyl groups can be used to increase the number of sites available for crosslinking. Amino acids and other biomolecules can be used to modify biological properties. Aromatic groups, aliphatic groups, and halogen atoms can be used to modify interchain interactions within the polymer.

[0011] Alternatively, the polymer backbone of the prepolymer is a polyamide backbone or a polyurethane backbone. For example, a polyamine (containing two or more amino groups) can be used, either together with a polyol or after reacting with a polyol, followed by reaction with a polyacid. Exemplary poly(ester amides) include those described in Cheng et al., Adv. Mater. 2011, 23, 1195-11100, the contents of which are incorporated herein by reference. In another example, a polyisocyanate (containing two or more isocyanate groups) can be used, either together with a polyol or after reacting with a polyacid. Exemplary polyester urethanes include those described in U.S. Patent Application Publication No. 2013 / 231412.

[0012] The weight average molecular weight (Mw) of the prepolymer, as measured by gel permeation chromatography with refractive index, may be from about 1,000 daltons to about 1,000,000 daltons, preferably from about 2,000 daltons to about 500,000 daltons, more preferably from about 2,000 daltons to about 250,000 daltons, and most preferably from about 2,000 daltons to about 100,000 daltons. The weight average molecular weight may be less than about 100,000 daltons, less than about 75,000 daltons, less than about 50,000 daltons, less than about 40,000 daltons, less than about 30,000 daltons, or less than about 20,000 daltons. The weight average molecular weight may be about 1,000 to about 10,000 daltons, about 2,000 to about 10,000 daltons, about 3,000 to about 10,000 daltons, or about 5,000 to about 10,000 daltons, preferably about 4,500 daltons. As used herein, the term "about" means within 10%, preferably within 8%, and more preferably within 5% of a given numerical value or range. According to a specific embodiment, "about X" means X, where X refers to a numerical value or range.

[0013] The prepolymer may have a polydispersity, as measured by gel permeation chromatography with refractive index, of less than 20.0, more preferably less than 10.0, more preferably less than 5.0, and even more preferably less than 2.5, preferably about 2.5. In the prepolymer, the molar ratio of polyol to polyacid is suitably in the range of about 0.5:1 to about 1.5:1, preferably in the range of about 0.9:1.1 to about 1.1:0.9, and most preferably about 1:1.

[0014] Activated Prepolymer The prepolymer in the composition of the present invention has activated groups on its polymer backbone. An activated group is a functional group that can react to form crosslinks, or a functional group that can react to form crosslinks. A prepolymer is activated by providing one or more functional groups on the monomer units of the backbone with functional groups that react or can react to form crosslinks that result in a cured polymer. According to embodiments, the prepolymer has activated groups of different nature on the monomer units of its backbone. The polymer backbone of the prepolymer has the general formula (-AB-) n wherein A is derived from a substituted or unsubstituted polyol or a mixture thereof, and B is derived from a substituted or unsubstituted polyacid or a mixture thereof.

[0015] Suitable functional groups to be activated on the prepolymer backbone include hydroxy groups, carboxylic acid groups, amines, and combinations thereof, preferably hydroxy and / or carboxylic acid. Free hydroxy or carboxylic acid groups on the prepolymer can be activated by functionalizing the hydroxy groups with moieties capable of forming crosslinks between polymer chains. The activated groups can be free hydroxy or carboxylic acid groups on the A and / or B portions of the prepolymer. The free hydroxyl or carboxylic acid groups can be functionalized with various functional groups, for example, vinyl groups. The vinyl groups can be introduced by various techniques known in the art, for example, by vinylation or acrylation. According to the present invention, the vinyl groups have the following structure: -CR x =CR y R z wherein R x , R y , R z are each independently selected from the group consisting of H, alkyl such as methyl or ethyl, aryl such as phenyl, substituted alkyl, substituted aryl, carboxylic acid, ester, amide, amine, urethane, ether, and carbonyl.

[0016] Preferably, the activated group is or contains an acrylate group. According to the present invention, the acrylate group may contain the following group: -C(=O)-CR p =CR q R r , where R p , R q , R r are independently selected from the group consisting of H, alkyl such as methyl or ethyl, aryl such as phenyl, substituted alkyl, substituted aryl, carboxylic acid, ester, amide, amine, urethane, ether, and carbonyl. According to an embodiment, the activated prepolymer contains a mixture of different acrylate groups. Preferably, -C(=O)-CR p =CR q R r For all or part of the acrylate group containing the R p , R q and R r is H; or R p is CH3 and R q and R r is H; or R p and R q is H and R r is CH3; or R p and R q is H and R r is phenyl. Vinyl groups can also be incorporated into the prepolymer backbone by using free carboxyl groups on the prepolymer. For example, hydroxyethyl methacrylate can be incorporated through the COOH groups of the prepolymer using carbonyldiimidazole activation chemistry.

[0017] In embodiments of the present invention, at least a portion of the activated groups on the polymer backbone of the prepolymer may be alkene groups (e.g., acrylate, methacrylate). The degree of activation (e.g., acrylation) may be determined by: 1The degree of activation (e.g., acrylation) is preferably characterized as "DA." The proportion of activated groups can be compared to the number of monomer units in the backbone. To achieve optimal bust performance properties at room temperature or elevated temperatures up to 40°C (preferably 37°C), this proportion can be varied and may be 0.1 to 0.8 moles per mole of monomer unit, preferably 0.2 to 0.6 moles per mole of monomer unit, and most preferably 0.3 to 0.45 moles per mole of monomer unit, e.g., 0.3 moles per mole of monomer unit. It is most preferred when the degree of activation is as described above and the reactive functional group is an acrylate (i.e., the degree of acrylation is as described above). The polymer units in the backbone have the general formula (-AB-) n where A is derived from a substituted or unsubstituted polyol and B is derived from a substituted or unsubstituted polyacid, the monomer unit has the general formula -AB-, and the percentage of activated groups can be expressed per mole of polyacid or per mole of polyol. The DA ranges given above are preferably moles / mole of polyacid.

[0018] The prepolymer in the composition of the present invention preferably has the general formula (I): [ka] (I) The activated prepolymer has the formula: In the formula, n and p each independently represent an integer of 1 or greater, and R2 in each unit is hydrogen, a polymer chain, -C(=O)-CR3=CR4R5, or C(=O)NR6-CR7R8-CR9R 1O -OC(=O)-CR3=CR4R5 (wherein R3, R4, R5, R6, R7, R8, R9 and R 1O are each independently selected from the group consisting of H, alkyl such as methyl or ethyl, aryl such as phenyl, substituted alkyl, substituted aryl, carboxylic acid, ester, amide, amine, urethane, ether, and carbonyl).

[0019] Preferably, R3, R4 and R5 are H, or R3 is CH3 and R4 and R5 are H, or R3 and R4 are H and R5 is CH3; or R3 and R4 are H and R5 is phenyl. Preferably, R6, R7, R8, R9 and R 1O is H. Preferably, p is an integer of 1 to 20, more preferably an integer of 2 to 10, and even more preferably an integer of 4 to 10. It is most preferable when p=8.

[0020] Preferably, the prepolymer in the composition of the present invention has the general formula (II): [ka] (II) is derived from an activated prepolymer containing monomer units of In the formula, n represents an integer of 1 or more.

[0021] More preferably, the prepolymer in the composition of the present invention has the general formula (II): [ka] (II) derived from an activated prepolymer having monomer units of In the formula, n represents an integer of 1 or more.

[0022] In addition to acrylate or other vinyl groups, other reagents can be used to provide activated groups on the prepolymer backbone. Examples of such reagents include, but are not limited to, glycidyl, epichlorohydrin, triphenylphosphine, diethyl azodicarboxylate (DEAD), diazirine, divinyl adipate, and divinyl sebacate, phosgene-based reagents, diacid chlorides, bis-anhydrides, bis-halides, metal surfaces, and combinations thereof, used with enzymes as catalysts. The reagents may further include isocyanate, aldehyde, epoxy, vinyl ether, thiol, DOPA residue, or N-hydroxysuccinimide functional groups.

[0023] Zeta Potential-Activated and Functionalized Prepolymers The inventors have found that there is a positive correlation between the zeta potential of a composition and the adhesive strength of the composition after curing. The zeta potential of the compositions of the present invention can vary depending on the prepolymer used, including the compositional makeup of the prepolymer. "Zeta potential" means the electrical charge, measured in millivolts (mV) or volts (V), that develops at the interface between a solid surface and its liquid medium. Zeta potential is the potential difference formed between the dispersion medium and the stationary layer of fluid that adheres to the dispersed particles in the interfacial double layer. The magnitude of the zeta potential indicates the degree of electrostatic repulsion between adjacent particles of the same charge in a dispersed system. The zeta potential of the composition is influenced by the number and nature of the charged atoms in the prepolymer, but also by other charged species that may be present in the composition. Thus, the prepolymers of the present invention are not only activated by introducing functional groups capable of forming crosslinks, preferably acrylate groups, but are also functionalized with charged atoms.

[0024] In a preferred embodiment of the present invention, at least a portion of the activated groups (e.g., acrylate) on the polymer backbone of the prepolymer are reacted with a compound containing a charged or chargeable atom, preferably a compound containing a charged heteroatom, more preferably a compound containing a positively charged heteroatom, hereinafter referred to as "activated functionalized groups." Additionally, at least a portion of the other groups (eg, hydroxyl groups, carboxyl groups) on the polymer backbone of the prepolymer may contain charged heteroatoms, preferably positively charged heteroatoms. The positively charged heteroatom on the prepolymer may be derived from any element other than carbon or hydrogen. Preferred positively charged heteroatoms are nitrogen, phosphorus, and sulfur. Most preferably, the positively charged heteroatom is a positively charged nitrogen atom.

[0025] In the compositions of the present invention, the proportion of activated functional groups (i.e., activated groups modified to contain a charged atom, preferably a charged heteroatom, more preferably a positively charged heteroatom) relative to the number of monomer units in the backbone may vary from polymer to polymer, and may suitably be in the range of about 0.05 to about 0.4 moles per mole of monomer unit, preferably about 0.09 to about 0.25 moles per mole of monomer unit. 1 The polymer units in the main chain are of the general formula (-AB-) nwhere A is derived from a substituted or unsubstituted polyol and B is derived from a substituted or unsubstituted polyacid, the monomer units are of the general formula -AB-, and the proportion of activated functional groups can be expressed per mole of polyacid or per mole of polyol. The ranges given above are preferably moles / mole of polyacid. When the functionalized groups (including activated functionalized groups) on the backbone monomer of the prepolymer that contain a positively charged heteroatom are positively charged nitrogen atoms, the portion of the functionalized groups containing a positively charged heteroatom is preferably characterized as "DN+." DN+ is the number of positively charged nitrogen atoms relative to the number of monomer units in the backbone. The DN+ parameter utilizes the characteristic peak of the hydrogen atom adjacent to the positively charged nitrogen atom. 1 It is preferably measured by H-NMR spectroscopy. The DN+ parameter is preferably expressed in moles / mole of polyacid.

[0026] The activated functionalizing group containing a positively charged nitrogen atom is preferably of the general formula (III): [ka] (III) and In the formula, R a , R b , R c , R d , R e and R f are independently selected from H, alkyl, alkenyl and aryl, preferably R d , R e and R f At least one of is H.

[0027] R a , R b , R c , R d , R e and R fThe alkyl groups for are suitably selected from the group consisting of straight chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched chain alkyl groups (e.g., isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), and alkyl-substituted cycloalkyl groups. Preferably, any alkyl group is selected from the group consisting of C 1-8 Alkyl groups, more preferably C 1-4 It is an alkyl group, most preferably a methyl or ethyl group. R a , R b , R c , R d , R e and R f The alkenyl group for is suitably selected from the group consisting of straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl- or alkenyl-substituted cycloalkenyl groups, and cycloalkyl- or cycloalkenyl-substituted alkenyl groups. Preferably, any alkenyl group is selected from the group consisting of C 2-8 It is an alkenyl group.

[0028] R a , R b , R c , R d , R e and R f The aryl group for is preferably selected from the group consisting of 5-membered monocyclic aromatic groups, 6-membered monocyclic aromatic groups, and polycyclic, such as tricyclic or bicyclic, aryl groups (e.g., naphthalene, anthracene, phenanthrene, etc.). The aryl group can also be fused or bridged with, for example, a non-aromatic alicyclic or heterocyclic ring to form a polycycle, etc. Preferably, R a is hydrogen. Preferably, R b is hydrogen. Preferably, R cis hydrogen. Preferably, R d , R e and R f One, two or three of R are hydrogen. Most preferably, R d , R e and R f In another embodiment, one of R d , R e and R f is not hydrogen.

[0029] Alternatively, the activated functionalizing group containing a positively charged nitrogen atom is preferably of the general formula (IV): [ka] (IV) and In the formula, R a , R b , R c , R d , R e and R f is as defined above for the group of formula (III), and n represents an integer of 1 or more, preferably an integer of 1 to 4.

[0030] According to a preferred embodiment, the activated functionalizing group of general formula (IV) is [ka] is.

[0031] According to another embodiment, the positively charged heteroatom is phosphorus or sulfur. Examples of activated functional groups containing a positively charged sulfur atom or a positively charged phosphorus atom are represented by the general formula (V) or (VI): [ka] (V)

[0032] [ka] (VI) may be In the formula, R a , R b , R c , R d , R e and R f is as defined above for the group of formula (III).

[0033] In preferred embodiments, the charged atoms of the prepolymer are present on activated (e.g., acrylated) groups on the backbone, and charged atoms can also be present on the backbone (e.g., on hydroxy groups, on carboxyl groups, as substitutions on polyols of polyacids).

[0034] In an embodiment of the present invention, the prepolymer has the general formula (VII): [ka] (VII) and In the formula, p is 1 to 20, n, m, and o are integers greater than 1, and R a , R b , R c , R d , R e and R f is as defined above for the group of formula (III). p is preferably 2 to 10, more preferably 4 to 10, and most preferably p=8. n, m, and o are integers greater than 1. The values ​​of n, m, and o are preferably large enough so that the prepolymer has a weight average molecular weight as described above, for example, from about 1,000 daltons to about 1,000,000 daltons.

[0035] According to the prepolymer of general formula (VII), some hydroxy groups on the main chain monomer units are activated with acrylate groups, and some are activated functional groups containing charged heteroatom groups (including positively charged nitrogen atoms). The preferred ratio of n:m:o will be determined by the preferred content of activated groups and activated functional groups.

[0036] In another embodiment of the present invention, the prepolymer has the general formula (VIII): [ka] (VIII) and In the formula, p, q, and r are integers from 1 to 20, n, m, and o are integers greater than 1, and R a , R b , R c , R d , R e and R f is as defined above for the group of formula (III).

[0037] p is preferably 2 to 10, more preferably 4 to 10, and most preferably p=8. q is preferably 1 to 4, and most preferably q is 2. r is preferably 1 to 4, and most preferably r is 2. n, m, and o are integers greater than 1. The values ​​of n, m, and o are preferably large enough so that the prepolymer has a weight average molecular weight as described above, for example, from about 1,000 daltons to about 1,000,000 daltons.

[0038] According to the prepolymer of general formula (VIII), some hydroxy groups on the main chain monomer units are activated with acrylate groups, and some are activated functional groups containing charged heteroatom groups (including positively charged nitrogen atoms). The preferred ratio of n:m:o will be determined by the preferred content of activated groups and activated functional groups.

[0039] Zeta potential measurement The zeta potential can be measured for compositions of the present invention using the following protocol. The device used to measure the zeta potential is a Zetasizer Nano-ZS Zen 3600. A Malvern zeta potential cell DTS1070 is used. Prepare a standard solution by weighing 15 mg of prepolymer into a glass vial. Add 50 μL of isopropanol and 1 mL of deionized water. Vortex the solution to completely dissolve the prepolymer. Transfer 50 μL of the resulting solution to a 20 mL glass vial and add 5 mL of deionized water.

[0040] Add 1 mL of the solution to the zeta potential cell and place the cell in the Zetasizer instrument. Set the instrument to "Manual" followed by "Measurement Type - Zeta Potential Sample" with the following selections: Material - Polystyrene Latex, Dispersant - Water, General Options - Smoluchowski Model, Temperature - 37°C, Equilibration Time - 120 seconds, Cell - Disposable Collapsible Capillary Cell. Three measurements are performed under automatic mode with a minimum of 10 runs and a maximum of 100 runs. Three measurements are performed per sample with zero delay between measurements. In the composition of the present invention, the zeta potential (measured according to the protocol described above) is 0 to about 45 mV, preferably about 5 to about 40 mV, and more preferably about 5 to about 30 mV.

[0041] composition The compositions of the present invention can be prepared in the presence of and / or mixed with colorants, preferred examples of which include those recommended by the FDA for use in medical devices, pharmaceuticals, or cosmetics. Likewise, the composition may further include a stabilizer, such as MEHQ or N-phenyl-2-naphthylamine (PBN).

[0042] The activated and functionalized prepolymers of the composition can be further reacted with one or more additional materials to modify the crosslinks between the polymer chains, for example, before or during curing / crosslinking, one or more hydrogel or other oligomeric, monomeric, or polymeric precursors (e.g., precursors that can be modified to contain acrylate groups), such as poly(ethylene glycol), dextran, chitosan, hyaluronic acid, alginate; other acrylate-based precursors, such as acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, methyl acrylate, ethyl acrylate, acrylonitrile, n-butanol, methyl methacrylate, acrylic anhydride, methacrylic anhydride; Other compounds that can be reacted with the acrylated prepolymer include TMPTA, trimethylolpropane trimethacrylate, pentaerythritol trimethacrylate, pentaerythritol tetramethacrylate, ethylene glycol dimethacrylate, dipentaerythritol pentaacrylate, Bis-GMA (bisphenol A glycidyl methacrylate), TEGDMA (triethylene glycol dimethacrylate), sucrose acrylate; other thiol-based precursors (monomers or polymers); other epoxy-based precursors; and combinations thereof.

[0043] The compositions of the present invention may be surgical compositions suitable for use as tissue sealants and / or adhesives, having flow properties that allow them to be applied to the desired area via syringe or catheter, yet being sufficiently viscous to remain at the application site without being washed away by bodily fluids (e.g., water and / or blood). Preferably, the viscosity of the composition is 500-100,000 cP, more preferably 1,000-50,000 cP, even more preferably 2,000-40,000 cP, and most preferably 2,500-25,000 cP. Viscosity analysis is performed using a Brookfield DV-II+ Pro viscosimeter equipped with a 2.2 mL chamber and an SC4-14 spindle, varying the speed from 5 to 80 rpm during analysis. The above-mentioned viscosities exist within the temperature range relevant for medical applications (i.e., room temperature to 40°C, preferably 37°C).

[0044] The compositions of the present invention can be incubated in bodily fluids such as blood prior to administration and hardening, and do not substantially lose adhesive strength when hardened. The compositions of the present invention are preferably stable in body fluids, such as blood, and more particularly, the compositions of the present invention preferably do not spontaneously crosslink in body fluids without the presence of a deliberately applied stimulus to initiate crosslinking, e.g., light, such as UV light, heat, or a chemical initiator. The compositions can be cured using free radical initiation, for example, by photoinitiated polymerization, thermally initiated polymerization, or redox initiated polymerization.

[0045] Preferably, to promote the reaction, the composition is irradiated with light, such as ultraviolet (UV) light, in the presence of a photoinitiator. Examples of suitable photoinitiators include 2-dimethoxy-2-phenyl-acetophenone, 2-hydroxy-1-[4-(hydroxyethoxy)phenyl]-2-methyl-1-propanone (Irgacure 2959), 1-hydroxycyclohexyl-1-phenyl ketone (Irgacure 184), 2-hydroxy-2-methyl-1-phenyl-1-propanone (Darocur 1173), 2-benzyl-2-(dimethylamino)-1-[4-morpholinyl)phenyl]-1-butanone (Irgacure 369), benzoylguanidine, and the like. methyl ester (Darocur MBF), oxy-phenyl-acetic acid-2-[2-oxo-2-phenyl-acetoxy-ethoxy]-ethyl ester (Irgacure 754), 2-methyl-1-[4-(methylthio)phenyl]-2-(4-morpholinyl)-1-propanone (Irgacure 907), diphenyl(2,4,6-trimethylbenzoyl)-phosphine oxide (Darocur TPO), phenylbis(2,4,6-trimethylbenzoyl)phosphine oxide (Irgacure 819), and combinations thereof.

[0046] Preferably, to promote the reaction, the composition is irradiated with visible light (typically blue or green light) in the presence of a photoinitiator. Examples of photoinitiators for visible light include, but are not limited to, diphenyl(2,4,6-trimethylbenzoyl)-phosphine oxide, eosin Y disodium salt, N-vinyl-2-pyrrolidone (NVP), triethanolamine, and camphorquinone. In applications of the compositions, including in vivo photopolymerization and other medical applications, the use of a cytocompatible photoinitiator is preferred and may be required by regulatory agencies. The photoinitiator Irgacure 2959 can be used, which causes minimal cytotoxicity (cell death) across a wide range of mammalian cell types and species. For photopolymerization to occur, the composition (and, if applicable, the substrate to which it is applied) is preferably sufficiently transparent to light.

[0047] In applications where the composition cures in vivo, the temperature at which curing occurs is preferably controlled so as not to damage the tissue to which the composition is applied. Preferably, the composition is heated during irradiation to no more than 45°C, more preferably no more than 37°C, and even more preferably no more than 25°C. In addition to photochemical crosslinking, the compositions can be thermally cured by the Mitsunobu reaction, by redox pair initiated polymerization (e.g., benzoyl peroxide, N,N-dimethyl-p-toluidine, ammonium persulfate, or tetramethylenediamine (TEMED)), and by the Michael addition reaction using bifunctional sulfhydryl compounds.

[0048] In one embodiment, the redox composition (i.e., a composition that can be thermally cured by redox-initiated radical polymerization) can include 0.1 to 5 wt % of a reducing agent (e.g., 4-N,N-trimethylaniline, N,N-bis(2-hydroxyethyl)-p-toluidine, N,N-dimethylaniline, N,N-diethylaniline, sodium p-toluenesulfonate, or N-methyl-N-(2-hydroxyethyl)-p-toluidine); 0 to 5 wt % of an oxygen inhibitor (e.g., 4-(diphenylphosphino)styrene or triphenylphosphine); 0.005 to 0.5 wt % of a working time agent (e.g., Tempol or 4-methoxyphenol); and 0.1 to 10 wt % of an oxidizing agent (e.g., ammonium persulfate, potassium persulfate, or benzoyl peroxide). The initiation of the redox-initiated polymerization is affected by the absolute and relative amounts of the different reagents.

[0049] Upon polymerization, the activated and functionalized prepolymer forms a crosslinked network with improved adhesive properties and exhibits significant adhesive strength, even in the presence of blood and other bodily fluids. After curing, the resulting cured polymer is preferably sufficiently elastic to resist movement of the underlying tissue (e.g., cardiac or vascular contractions). The adhesive can provide a seal that prevents fluid and gas leakage. The adhesive is preferably biodegradable and biocompatible, and induces a minimal inflammatory response. The adhesive is preferably elastomeric. Biodegradation can be assessed in vitro, for example, in phosphate buffered saline (PBS) or under acidic or alkaline conditions. Biodegradation can also be assessed in vivo, for example, in animals (e.g., mice, rats, dogs, pigs, or humans). The degradation rate can be assessed by measuring the loss of polymer mass over time in vitro or in vivo.

[0050] The cured composition, alone or coated onto a patch or tissue, has a resistance of at least 0.5 N / cm 2 , preferably at least 1 N / cm 2 , more preferably at least 2 N / cm 2 , e.g., 1.5N / cm 2 ~2N / cm 2 However, preferably 5N / cm 2 Larger, e.g., 6N / cm 2 or 7N / cm 2 Preferably, the adhesive exhibits a 90° pull-off adhesive strength of up to or greater than 1000 psi. Pull-off adhesive strength refers to the adhesive force obtained by applying an adhesive article or sample to moist tissue, e.g., the epicardial surface of vascular or cardiac tissue immobilized on a flat substrate such as a metal stub. The 90° pull-off adhesive test determines the maximum normal force (tension) that a surface area can withstand before the adhesive detaches (N. Lang et al., Sci. Transl. Med., 2014, 6, 218ra6). According to a preferred embodiment, the compositions of the present invention are cured in light in the presence of a photoinitiator, and the cured composition has a viscosity of at least 0.5 N / cm2 , preferably at least 1 N / cm 2 , more preferably at least 2 N / cm 2 , e.g., 1.5N / cm 2 ~2N / cm 2 However, preferably 5N / cm 2 Larger, e.g., 6N / cm 2 or 7N / cm 2 exhibits a 90° pull-off adhesive strength of up to or greater than 90°.

[0051] The hardened composition also desirably exhibits a burst pressure greater than 100 mmHg, preferably in the range of 400 mmHg to 600 mmHg or greater, e.g., 400 mmHg or 500 mmHg. Burst pressure or burst force refers to the pressure value obtained by bursting an explanted porcine carotid artery vessel having an incision coated with the composition. The compositions of the present invention, when cured with light in the presence of a photoinitiator, preferably exhibit one or more of the following properties: i) 0.5N / cm 2 Higher, preferably 2 to 7 N / cm 2 or greater 90° pull-off adhesive strength, and ii) A burst capacity of more than 100 mmHg, preferably 200 to 300 mmHg or more.

[0052] According to a preferred embodiment, the compositions of the present invention are used as adhesives (i.e., capable of strongly bonding to surfaces or bonding one surface to another after curing). According to another embodiment, the compositions of the present invention are used as sealants (i.e., capable of preventing leakage of fluids, gases, etc. by forming a barrier or filling void volume after curing). In addition to adhering and sealing wet biological tissue, the compositions may adhere and seal a variety of natural or synthetic, hydrophilic or hydrophobic substrates, such as polyethylene terephthalate, expanded polyethylene terephthalate, polyester, polypropylene, silicone, polyurethane, acrylic, fixed tissue (e.g., pericardium), ceramics, or any combination thereof.

[0053] Preparation method The process for preparing the compositions of the present invention comprises several essential steps, but may be subject to several variations. According to a preferred embodiment, the process comprises: i) polymerizing a monomer to provide a prepolymer backbone; ii) activation of the backbone monomer units to provide an activated prepolymer; and iii) functionalizing the activated prepolymer with a compound containing a charged atom or a chargeable atom to provide an activated and functionalized prepolymer. The monomers are preferably Component A (a polyol or a mixture of polyols) and Component B (a polyacid or a mixture of polyacids), suitably added together in a molar ratio ranging from 0.5:1 to 1.5:1, preferably 0.9:1.1, and most preferably 1:1. When Component A is glycerol and Component B is sebacic acid, added in a 1:1 molar ratio, there are three hydroxyl groups in the glycerol for every two carboxyl groups in the sebacic acid. Therefore, the extra hydroxyl groups in the glycerol can be used for activation, just like the terminal carboxylic acid groups.

[0054] Conditions for step i) include a temperature range of 100 to 140°C (preferably 120 to 130°C), an inert atmosphere (preferably containing nitrogen), and a vacuum. In a preferred embodiment, hydroxy or carboxyl groups are present on the prepolymer backbone obtained after step i). Activation in step ii) is suitably achieved by acrylation of the prepolymer backbone. In a preferred embodiment, activation is carried out via acrylation of a hydroxy or carboxyl group. Activation of the carboxyl can result in the formation of an anhydride, which can be completely or partially removed (e.g., using ethanol) (see, e.g., WO2016 / 202984).

[0055] One or more acrylates may be used as the acrylating agent. The acrylates may contain the following group: -C(=O)-CR p =CR q R r , where R p , R q , R r are each independently selected from the group consisting of H, alkyl such as methyl or ethyl, aryl such as phenyl, substituted alkyl, substituted aryl, carboxylic acid, ester, amide, amine, urethane, ether, and carbonyl. p is H. Most preferably, the acrylating agent is acryloyl chloride. Step ii) can be carried out in the presence of one or more solvents or catalysts, examples of which include dichloromethane (DCM), ethyl acetate (EtOAc), dimethylaminopyridine (DMAP), triethylamine (TEA), or any combination thereof. Several purification steps may be carried out at this stage, preferably 2 to 11 water washing steps, preferably 2 to 8 times, most preferably 8 times. Alternatively, the activation in step ii) may be acrylation using an acrylic isocyanate compound. A preferred acrylic isocyanate compound is 2-isocyanatoethyl (meth)acrylate.

[0056] For the functionalization of step iii), in a preferred embodiment, amine moieties are grafted onto the prepolymer backbone, followed by acidification to form charged amines. Amine grafting can be carried out via specific substituents of the activated prepolymer, onto hydroxy, carboxyl, or activated (eg, acrylate) groups. According to a preferred embodiment, the acrylate groups are reacted with an amine to give grafted tertiary amine groups, and the resulting amines are acidified to give ammonium groups (see C1.3 in the Examples). According to another preferred embodiment, the amine is alternatively or additionally modified to an anhydride during an activation step before being grafted onto the carboxylic acid (see C1.5 in the Examples), in this case forming an amide. According to another preferred embodiment, the amine is alternatively or additionally grafted onto a modified carboxylic acid (e.g., by modification to an acid anhydride) in order to more easily react with a nucleophile, such as any bifunctional molecule bearing an alcohol and an amine group, more preferably diethylethanolamine (see C1.6 in the Examples).

[0057] According to the present invention, the amine may be a primary amine, a secondary amine or a tertiary amine. Preferred amines include ethylamine. The amination in step iii) is preferably carried out in a solvent such as dichloromethane. Charging of the amine can be carried out via acidification, which is preferably carried out in the presence of an acid such as a carboxylic acid or hydrochloric acid. Examples of carboxylic acids include formic acid and acetic acid. According to certain embodiments, the activation of step ii) and the functionalization of step iii) may occur in the same reaction step without the need for acidification. At least one additive may be added to the composition obtained in step iii), in a preferred embodiment said additive is selected from the group consisting of photoinitiators, radical inhibitors and dyes.

[0058] According to a preferred embodiment, the method further comprises one or more purification steps iv) to ensure that the composition is free of solvents, by-products, impurities or unreacted materials. Such purification steps may be carried out throughout any reaction step or by applying one or more purification techniques during the preparation of the composition. In a preferred embodiment, such a purification step may include washing in an aqueous medium. Phase separation during the water wash can be improved by using a salt that is solubilized in the aqueous phase (e.g., about 50 to about 500 g / L aqueous salt solution, preferably about 300 g / L aqueous salt (e.g., sodium chloride) solution). According to a preferred embodiment, the water wash is a brine wash. Examples of salts include, but are not limited to, sodium chloride or potassium chloride. According to a preferred embodiment, such purification step can be carried out by solvent evaporation or by supercritical carbon dioxide extraction.

[0059] use Tissue adhesion and sealing The compositions of the present invention can be used to bond or seal target surfaces, including tissue, implant materials such as PTFE-based implants, or any combination thereof. A method for bonding or sealing a target surface includes applying the composition to the surface and allowing the composition to cure. Unlike conventional tissue adhesives that spontaneously activate during application or in the presence of water, or that are hydrophilic and therefore require washing off before setting, the compositions of the present invention can be applied to wet substrates without activation or replacement. They can also be applied to dry substrates. The composition can also be used to adhere tissue to the surface of a medical device. The composition can be used in a medical device, as part or all of the device, or to adhere a device to tissue. A method for adhering tissue to the surface of a medical device includes applying the composition to the tissue and / or the surface of the medical device and allowing the composition to harden. The composition can also be used to join tissues, including one or more in vivo tissues.

[0060] Surgical adhesives containing the compositions of the present invention can also be used for other purposes. Examples of uses include stopping bleeding resulting from wounds, trauma, etc., and during surgery (e.g., after suturing an implant to a blood vessel or after vascular access in endovascular treatment). The adhesive degrades over time, eliminating the need for removal before a surgeon sutures a closed wound. Other types of wounds that can be treated include, but are not limited to, leaking wounds, wounds that are difficult to close, or wounds that fail to heal properly via normal physiological mechanisms. The adhesive can be applied internally or externally for human or animal use. The composition of the present invention can also be used to create biodegradable stents. Stents can increase blood flow through blood vessels by increasing their diameter. However, because the stent is biodegradable, it can increase the diameter of the blood vessel while reducing the risk of thrombosis or covering the stent with scar tissue, which could narrow the blood vessel again. The composition can coat the outer surface of the stent to help adhere the stent to the blood vessel wall in a manner that is less damaging to tissue than an uncoated stent, or to prevent stent migration within the body. Similarly, the composition can coat the surface of any device that comes into contact with tissue to provide a suitable interface for adhesion to the tissue.

[0061] The compositions of the present invention can be used in a variety of other applications requiring an adhesive or sealant. Other uses include, but are not limited to, preventing air leaks after lung resection; reducing surgical time; sealing the dura mater; facilitating laparoscopic procedures; as a degradable skin adhesive; as a hernia matrix to prevent or reduce the need for stapling or tacks; preventing blood loss; manipulating organs and tissues during surgery; ensuring a corneal graft stays in place; patching the heart to reduce its dilation after a myocardial infarction and / or to deliver drugs; adhering another material to tissue; augmenting sutures or staples; distributing force across tissue; preventing leakage; as a barrier film on the skin to prevent evaporation of moisture from burned skin; as a patch for delivering anti-scar or antibacterial drugs; adhering devices to tissue; as a tape to adhere devices to mucosa to secure devices in the mouth (e.g., to retain dentures or oral appliances); as a tape to attach soft tissue to bone; preventing hole formation in tissue; and strengthening / increasing the mechanical properties of tissue.

[0062] Delivery of bioactive molecules The compositions of the present invention described may also include one or more medicinal, therapeutic, prophylactic, and / or diagnostic agents that are released during the period in which the material functions as a sealant / adhesive. The agent may be a small molecule drug (e.g., a small molecule drug having a molecular weight of less than 2000 Daltons, less than 1500 Daltons, less than 1000 Daltons, less than 750 Daltons, or less than 500 Daltons), a biomolecule (e.g., a peptide, protein, enzyme, nucleic acid, polysaccharide), a growth factor, a cell adhesion sequence (e.g., an RGD sequence or an integrin), an extracellular matrix component, or a combination thereof. Exemplary classes of small molecule drugs include, but are not limited to, anti-inflammatory drugs, analgesics, antimicrobial agents, and combinations thereof. Exemplary growth factors include, but are not limited to, TGF-β, acidic fibroblast growth factor, basic fibroblast growth factor, epidermal growth factor, IGF-I and II, vascular endothelial-derived growth factor, bone morphogenetic protein, platelet-derived growth factor, heparin-binding growth factor, hematopoietic growth factor, peptide growth factor, or nucleic acid. Exemplary extracellular matrix components include, but are not limited to, collagen, fibronectin, laminin, elastin, and combinations thereof. Proteoglycans and glycosaminoglycans can also be covalently or non-covalently associated with the compositions of the present invention.

[0063] tissue support The compositions of the present invention can be used to create tissue supports by forming molded articles inside the body to provide mechanical functions. Molded articles can be made by various fabrication techniques known in the art, including 3D printing. Such articles can perform functions such as holding two tissues together or positioning tissues in a specific location inside or outside the body. The lumen of a tissue, such as a blood vessel, can be coated with a layer of material to prevent restenosis, reclosure, or vasospasm following interventional treatment of the vessel. The composition may also include one or more types of cells, such as connective tissue cells, organ cells, muscle cells, nerve cells, and combinations thereof. The material may be seeded with one or more of tendon cells, fibroblasts, ligament cells, endothelial cells, lung cells, epithelial cells, smooth muscle cells, cardiac muscle cells, skeletal muscle cells, pancreatic islet cells, nerve cells, liver cells, kidney cells, bladder cells, urothelial cells, chondrocytes, and osteogenic cells. The combination of cells and materials can be used to support tissue repair and regeneration.

[0064] Anti-adhesion barrier The compositions of the present invention described herein can be applied to reduce or prevent the formation of adhesions after surgical procedures, for example, the compositions can be applied to prevent adhesion of brain tissue to the skull after brain surgery, or to the implantation of devices to prevent peritoneal adhesions. Other uses The compositions can also be used to coat tools, such as surgical instruments (e.g., forceps or hooks), to enhance the tool's ability to manipulate objects. The compositions can also be used in industrial applications (e.g., marine applications, such as underwater use or attachment to ship surfaces) where it is useful to have a biocompatible, degradable adhesive, for example, to reduce the potential toxicity of degradation products. The compositions can also be used to create molded articles by various techniques known in the art, including 3D printing. The molded articles can have microscale or nanoscale resolution. The present invention is illustrated by reference to the following examples, which are not intended to limit the invention in any way. [Example]

[0065] Example 1: Acrylic Functionalization (C1.4) (i) Synthesis of poly(glycerol sebacate) (PGS, C1.0): 1. Equal molar amounts of glycerol and sebacic acid were weighed out. 2. The temperature of the reaction mixture was set between 120 and 130°C until the monomer was completely melted. 3. After the reagents had melted, the bath or reaction temperature was lowered to a target value of 120°C and stirring was commenced. 4. The air in the flask was replaced with nitrogen by vacuum / purge cycle three times. 5. The reaction was continued for 8 hours. 6. The nitrogen supply was then removed and the pressure reduced using a vacuum pump set to a target of 15 mbar. The reaction was continued until the target Mw (approximately 3,000 Da) and polydispersity (<3) were achieved. The target molar ratio of glycerol:sebacic acid was 1:1, which was confirmed by nuclear magnetic resonance (NMR).

[0066] (ii) / (iii): Activation (acrylation) and functionalization of PGS (amination followed by acidification): The following procedure was used to activate the hydroxy groups on the PGS backbone. PGS (C1.0) was reacted with triethylamine (TEA ~0.4 g per g of PGS) and acryloyl chloride (AcCl ~0.37 g per g of PGS) in 10% (w / v) dichloromethane (DCM). Ethanol capping of acrylated PGS (C1.1) was achieved by overnight reaction with ethanol at temperatures ranging from 30 to 50 °C. The resulting prepolymer was purified by washing with water, preferably eight times, and distilled to obtain the prepolymer poly(glycerol sebacate) acrylate (PGSA, C1.2). The acrylated PGS was reacted with diethylamine (61 mg diethylamine (DEA) per gram of acrylated PGS) in dichloromethane at 40° C. for 5 hours to provide aminated and acrylated PGS (prepolymer C1.3). The aminated and acrylated PGS was acidified with acetic acid for 15 minutes at room temperature. The product was purified by washing with brine and distillation. The organic solution was concentrated to 50% (w / w). Additives (Irgacure TPO photoinitiator and radical inhibitor MEHQ) were added, and the product was purified by supercritical CO2 extraction. 1Using H NMR spectroscopy, the proportion of groups containing a positively charged nitrogen atom (DN+) and the proportion of groups containing acrylate groups (DA) were determined. DN+ was 0.18 moles / mole of polyacid, and DA was 0.31 moles / mole of polyacid. The final composition containing prepolymer C1.4 is a composition of the present invention.

[0067] Example 2: Acrylic Functionalization (C1.4) Synthesis of PGS(C1.0) The synthesis of PGS was carried out as described in Example 1. Activation and Functionalization of PGS - Acrylation, Amination and Acidification The following procedure was used to activate the hydroxy groups on the PGS backbone. PGS was reacted with triethylamine (TEA 0.4 g per g of PGS) and acryloyl chloride (AcCl 0.37 g per g of PGS) in 10% (w / v) dichloromethane to provide acrylated PGS. Ethanol capping of the acrylated PGS was achieved by reacting with ethanol overnight at temperatures ranging from 30 to 50 °C. The resulting prepolymer (C1.2) was purified by washing twice with water. The acrylated PGS was reacted with diethylamine (approximately 100 mg of DEA per gram of PGS) in dichloromethane at 40° C. for 5 hours, thereby providing aminated PGSA (C1.3). The aminated PGSA was acidified with acetic acid (2 molar equivalents relative to DEA) for 15 minutes at room temperature, and the product was purified by washing with brine and distillation. 1 Using H NMR spectroscopy, the proportion of groups containing a positively charged nitrogen atom (DN+) and the proportion of groups containing an acrylate group (DA) were determined to be 0.21 moles / mole of polyacid, and 0.38 moles / mole of polyacid. Additives (Irgacure TPO photoinitiator and radical inhibitor MEHQ) were added, and the product C1.4 was purified by supercritical CO extraction. The final DN+ was 0.21 moles / mole of polyacid, and the final DA was 0.29 moles / mole of polyacid (inventive composition containing prepolymer C1.4).

[0068] Example 3: Acrylate Functionalization and Simultaneous Anhydride Removal (C1.5) Synthesis of PGS(C1.0) The synthesis of PGS was carried out as described in Example 1. Activation and Functionalization of PGS - Acrylation, Amination and Acidification The following procedure was used to activate the hydroxy groups on the PGS backbone. PGS was reacted with triethylamine (0.4 g TEA per g PGS) and acryloyl chloride (0.37 g AcCl per g PGS) in 10% (w / v) dichloromethane to provide acrylated PGS. Instead of ethanol capping, diethylamine (approximately 170 mg DEA per gram of PGS) was used, which was added directly to the previous solution and stirred at room temperature for 20 hours, thereby providing removal of the aminated PGSA and anhydride in one step. The aminated PGS was acidified with acetic acid (2 molar equivalents of acetic acid relative to DEA) at room temperature for 15 minutes, and the product was purified by washing with brine and distillation. 1 The proportion of groups containing a positively charged nitrogen atom (DN+) and the proportion of groups containing an acrylate group (DA) were measured using H NMR spectroscopy. DN+ was 0.54 mol / mol polyacid, and DA was 0.20 mol / mol polyacid. Additives (Irgacure TPO photoinitiator and radical inhibitor MEHQ) were added, and the product was purified by supercritical CO2 extraction. The final DN+ was 0.20 mol / mol polyacid, and the final DA was 0.39 mol / mol polyacid (composition of the present invention containing prepolymer C1.5).

[0069] Example 4: Prepolymer Functionalization by Anhydride Elimination (C1.6) Synthesis of PGS(C1.0) The synthesis of PGS was carried out as described in Example 1. Activation and functionalization of PGS - acrylation, modification with N,N-diethylethanolamine, acidification The following procedure was used to activate the hydroxy groups on the PGS backbone. PGS (C1.0) was reacted with triethylamine (~0.4 g triethylamine (TEA) per g PGS) and acryloyl chloride (~0.37 g acryloyl chloride (AcCl) per g PGS) in 10% (w / v) dichloromethane (DCM) to provide acrylated PGS (C1.1). The activated prepolymer was functionalized by modifying the resulting acid anhydride with N,N-diethylethanolamine. N,N-Diethylethanolamine (82 mL) was added to 450 mL of acrylated PGS (C1.1). The mixture was heated to 40°C for 24 hours. The mixture was then purified by washing with brine, and the organic layer was dried and concentrated to a 50% (w / w) solution. Acetic acid (70 mL) was then added, and the mixture was stirred for 5 minutes. The organic layer was washed with brine, dried, and concentrated to a 50% (w / w) solution. An additive (Irgacure TPO photoinitiator) was added, and the batch was purified by solvent evaporation, and its adhesive performance was evaluated. For the inventive composition containing C1.6, the DA was 0.74 moles / mole of polyacid, but the final DN+ could not be determined.

[0070] Example 5: Prepolymer activation alternatives (C1.9 and C1.10) Synthesis of PGS(C1.0) The synthesis of poly(glycerol sebacate) was as described in Example 1. Activation (acrylation) and functionalization (amination followed by acidification) of PGS The following procedure was used to activate the hydroxy groups on the PGS backbone. PGS (C1.0) was reacted with acrylic isocyanate (∼0.306 g acrylic isocyanate per g PGS) in 20% (w / v) ethyl acetate to provide acrylated PGS (prepolymer C1.9). The resulting activated prepolymer was functionalized without intermediate purification steps by reacting with diethylamine in ethyl acetate (60 mg diethylamine per gram of activated PGS) at 55 °C for 5 hours. The functionalized and activated PGS was acidified with acetic acid (0.670 mL AcOH per gram of C1.9) at room temperature for 15 minutes. The product (C1.10) was purified by washing with brine and distillation. The organic solution was then concentrated to 50% (w / w). Additives (Irgacure TPO photoinitiator and radical inhibitor MEHQ) were added, and the product was purified by supercritical CO2 extraction. 1 Using H NMR spectroscopy, the proportion of groups containing a positively charged nitrogen atom (DN+) and the proportion of groups containing an acrylate group (DA) were determined. DN+ was 0.19 moles / mole of polyacid, and DA was 0.30 moles / mole of polyacid. The final product containing prepolymer C1.10 is a composition of the present invention.

[0071] Example 6: Simultaneous activation and functionalization (C1.7 and C1.8) Synthesis of PGS(C1.0) The synthesis of PGS was carried out as described in Example 1. Simultaneous activation and functionalization of PGS - simultaneous acrylation and amination PGS was dissolved in DCM and a base (TEA or DIPEA) was added (1.20 moles of base per mole of glycerol). In a second vial, AcCl was dissolved in DCM (1.15 moles of AcCl per mole of glycerol). Both vials were flushed three times with vacuum / nitrogen cycles. The vial containing the AcCl solution was cooled to 0°C and protected from light. The solution of PGS + base was added dropwise to the AcCl solution over approximately 3 hours. The solution was then allowed to warm to room temperature and left stirring for 1 hour. The solution was washed once with brine, dried over magnesium sulfate and filtered. Ethanol capping of acrylated PGS was achieved by reacting with ethanol at temperatures ranging from 30 to 50 °C overnight. Additives (Irgacure TPO photoinitiator and radical inhibitor MEHQ) were added, and the product was purified by supercritical CO2 extraction. Composition C1.7 preferentially uses the base triethylamine (TEA). Composition C1.8 preferentially uses the base N,N-diisopropylethylamine (DIPEA).

[0072] Example 7: Aminated Poly(trimethylolpropane ethoxylate-co-sebacate) Acrylate (Prepolymer C2.1) Synthesis of poly(trimethylolpropane ethoxylate-co-sebacate) (PTS, prepolymer C2.0) PTS is a polymer similar to PGS, except that instead of being prepared from sebacic acid and glycerol, PTS is prepared from sebacic acid and trimethylolpropane ethoxylate. First, the following general protocol was applied to synthesize poly(trimethylolpropane ethoxylate-co-sebacate) (PTS, prepolymer C2.0). 1. Equimolar amounts of trimethylolpropane ethoxylate and sebacic acid were weighed out. 2. The temperature of the reaction mixture was set between 120 and 130°C until the monomer was completely melted. 3. After the reagents had melted, the bath or reaction temperature was lowered to a target value of 120°C and stirring was commenced. 4. The vacuum / purge cycle was repeated three times to replace the air in the flask with nitrogen. 5. The reaction was allowed to continue for 8 hours. 6. The nitrogen supply was then removed and the pressure reduced using a vacuum pump set to a target of 15 mbar. The reaction was continued until the target Mw (approximately 8000 Da) and polydispersity (<2.5) were achieved. The target molar ratio of trimethylolpropane ethoxylate to sebacic acid was 1:1, as confirmed by nuclear magnetic resonance (NMR).

[0073] Activation and Functionalization of PTS - Acrylation, Amination, and Acidification (C2.1-C2.4) PTS was reacted with triethylamine (0.19 g TEA per g PTS) and acryloyl chloride (0.16 g AcCl per g PTS) in 10% (w / v) dichloromethane to provide acrylated PTS (prepolymer C2.1). Ethanol capping of the acrylated PTSA was achieved by reacting with ethanol at temperatures ranging from 30 to 50°C overnight. The resulting polymer was purified by washing with water and distilled. The acrylated PTS was reacted with diethylamine (0.035 mL DEA per gram of C2.1) in dichloromethane at 40° C. for 5 hours to provide the acrylated and aminated PTS (prepolymer C2.2). The resulting prepolymer was acidified (0.04 mL acetic acid per gram of C2.2) for 15 minutes at room temperature. The resulting prepolymer (Prepolymer C2.3) was purified by washing with water, brine and distillation. An additive was added (Irgacure TPO photoinitiator) and the product was purified by solvent evaporation. Compositions containing prepolymer C2.4 are compositions of the invention.

[0074] Example 8: Dual activation and functionalization of PGS (C1.11 and C1.12) Synthesis of PGS(C1.0) The synthesis of PGS was carried out as described in Example 1. Activation and functionalization of PGS - double acrylation followed by amination and acidification The following procedure was used to activate and functionalize the hydroxy groups on the polymer backbone. Under magnetic stirring, PGS (C1.0) was reacted with 2-isocyanatoethyl methacrylate (0.32 g / (1 g of C1.0)) and 2-isocyanatoethyl acrylate (0.14 g / (1 g of C1.0)) in 20% (w / v) ethyl acetate at 70°C for 16 hours to give C1.11. The reaction mixture was then cooled to ambient temperature. In the second step, the reaction mixture was heated to 55°C, and diethylamine (0.15 g / (1 g of C1.0)) was added. The mixture was stirred at 55°C for 5 hours. The mixture was cooled to ambient temperature, and acetic acid (0.18 g / (1 g of C1.0)) was added to the mixture and stirred for 5 minutes. The product was purified by washing with brine, dried over MgSO4, and filtered. The resulting solution was concentrated to 50% (w / w). Additives (Irgacure TPO photoinitiator and radical inhibitor MEHQ) were added, and the product was purified by supercritical CO2 extraction. 1 Using H NMR spectroscopy, the proportion of groups containing a positively charged nitrogen atom (DN+) and the proportion of groups containing methacrylate groups (DA) were determined. DN+ was 0.44 moles / mole of polyacid, and DA was 0.18 moles / mole of polyacid. The final product containing prepolymer C1.12 is a composition of the present invention.

[0075] Example 9: Acrylic Functionalization with Varying Acidification Process The acrylated PGS (C1.1) was reacted with diethylamine (66 mg diethylamine (DEA) per gram of acrylated PGS) in dichloromethane at 40°C for 5 hours to provide the aminated and acrylated PGS (C1.3). The aminated PGSA was acidified with acetic acid (6 molar equivalents relative to DEA) for 15 minutes at room temperature, and the product was purified by washing with brine and distillation. Additives (Irgacure TPO photoinitiator and radical inhibitor MEHQ) were added, and the product C1.17 was purified by supercritical CO2 extraction. 1 Using H NMR spectroscopy, the percentage of groups containing a positively charged nitrogen atom (DN+) and the percentage of groups containing an acrylate group (DA) were determined. The final DN+ was 0.21 moles / mole of polyacid, and the final DA was 0.30 moles / mole of polyacid. The final product, containing prepolymer C1.17, is a composition of the present invention.

[0076] Example 10: Acrylic Functionalization with Further Variations in the Acidification Process The acrylated PGS (C1.1) was reacted with diethylamine (66 mg diethylamine (DEA) per gram of acrylated PGS) in dichloromethane at 40°C for 5 hours to provide the aminated and acrylated PGS (C1.3). The aminated PGSA was washed with 1 M HCl brine (5 min under stirring before phase separation). The organic layer was then washed twice with brine. The organic layer was isolated, dried over MgSO4, and concentrated to 50% (w / w). Additives (Irgacure TPO photoinitiator and radical inhibitor MEHQ) were added, and the product C1.18 was purified by supercritical CO2 extraction. 1 Using H NMR spectroscopy, the percentage of groups containing a positively charged nitrogen atom (DN+) and the percentage of groups containing an acrylate group (DA) were determined. The final DN+ was 0.21 moles / mole of polyacid, and the final DA was 0.31 moles / mole of polyacid. The final product, containing prepolymer C1.18, is a composition of the present invention.

[0077] Example 11: Acrylic Functionalization with Further Variation of the Acidification Process The acrylated PGS (C1.1) was reacted with diethylamine (46 mg of diethylamine (DEA) per gram of acrylated PGS) in dichloromethane at 40°C for 23 hours to provide the aminated and acrylated PGS (C1.3). Under stirring, the aminated PGSA was acidified with formic acid (2 molar equivalents relative to DEA) at room temperature for 5 minutes. An additive (Irgacure TPO photoinitiator) was added and the product C1.19 was concentrated under reduced pressure. 1 Using H NMR spectroscopy, the percentage of groups containing a positively charged nitrogen atom (DN+) and the percentage of groups containing an acrylate group (DA) were determined. The final DN+ was 0.16 moles / mole of polyacid, and the final DA was 0.30 moles / mole of polyacid. The final product, containing prepolymer C1.19, is a composition of the present invention.

[0078] Adhesive performance The examples were tested for pull-off adhesion according to the following pull-off method. The pull-off adhesion test (at 90°) was performed on an Instron using fresh porcine epicardial tissue. The tissue was stored in phosphate-buffered saline to ensure it remained wet during testing. Unless otherwise specified, polyglycerol sebacate urethane (PGSU) patches were used for testing, and the patches were approximately 200 mm thick and 6 mm in diameter. Prior to adhesion testing, a thin layer of prepolymer with a thickness of approximately 200 μm was applied to the patch material. During the curing process, a non-adhesive material (a 9 mm high borosilicate glass rod) applied a compressive force of 3 N to the sample composition-coated patch. The non-adhesive material was connected to a UV light with standard adhesive tape around both the glass rod and a UV light guide (Lumen Dynamics Group Inc.). The borosilicate glass rod facilitated removal of the curing system from the patch without disturbing the patch / adhesive-tissue interface. The pull-off procedure involved grip separation at a rate of 8 mm / min, resulting in the detachment of a uniform patch from the tissue surface. Adhesion force was recorded as the maximum force observed before adhesive failure, when a sharp decrease in the measured stress was observed.

[0079] Adhesion values ​​for cured compositions prepared from the above-described prepolymers are provided in Table 1 below. [Table 1]

[0080] The above table shows that the adhesion values ​​obtained with cured compositions of the invention (C1.4, C1.5, C1.6, C1.7, C1.8, C1.10, C2.4, C1.12, C1.17, C1.18, C1.19) were superior to the adhesion values ​​obtained with cured compositions not of the invention (C1.2, C1.3, C2.1). Zeta potential compared to adhesive strength The zeta potential of the prepolymers of the present invention was measured using the protocol described above. The adhesion of cured prepolymer-based compositions was measured using the pull-off adhesion test described above. Figure 1 shows a plot of the zeta potential results against the adhesion results. The results show that increasing the zeta potential of the composition improves adhesion.

[0081] Example 12: Formulation of compositions (C1.13-C1.16): Crosslinking of polymers by redox Compositions were formulated using prepolymers C1.4 and C1.12 prepared as described above, and the formulations are summarized in Table 2 below. [Table 2]

[0082] BPO is benzoyl peroxide. MHPT is N-methyl-N-(2-hydroxyethyl)-p-toluidine. TMA is 4-N,N-trimethylaniline. DPPS is 4-(diphenylphosphino)styrene. Tempol is 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl. For example, for Examples C1.13, C1.14, C1.15 and C1.16, and Prepolymer C1.4, the Lap Shear Adhesion Performance Test was used.

[0083] The protocol was adapted from ASTM F2255.1422857-1 entitled "Standard Test Method for Strength Properties of Tissue Adhesives in Lap-Shear by Tension Loading" and was as follows: The tissue samples used were pig buttocks supplied by a local butcher and stored in a refrigerator (2-5°C). The lap shear tests were carried out on the same day. The muscle tissue was cut with a knife and scalpel to obtain rectangular specimens with the following dimensions: length = 3 cm, width = 1.5 cm, height = 0.2-0.4 cm. The tissue specimens were stored in PBS (maximum 2 hours) until testing. For each test, two pieces of muscle were removed from the PBS and placed on a paper towel on each side for 3 seconds to remove excess water. The tissue was still very wet. The test formulation was applied to one tip of one muscle sample with a spatula, as close to the edge as possible, with a formulation width of approximately 0.8-1.0 cm. The other muscle sample was then placed on top, with an overlap of 1.5 cm x 0.8-1.0 cm. The upper piece was placed in contact with the lower piece and gently pressed with a finger to bring the two muscle samples into contact. For light-activated formulations (e.g., C1.4 in the table below): The formulation was cured using an Omnicure Light (5 second cycle, 70% intensity). The overlap was exposed to light for at least 6 cycles. For the redox formulation: Wait until the remaining formulation in the microtube has completely hardened.

[0084] For all samples: The assembly was placed vertically, starting with the upper grip. Without pulling on the tissue, the lower grip was tightened. Displacement and load were set to zero, and the upper grip was raised at a rate of 5 mm / min until detachment of both muscle specimens. The load versus displacement curve was recorded, and the maximum load before detachment was recorded. At the end of the test, the area of ​​the compound was measured with a vernier caliper. This was easy to measure because the compound was blue and did not break apart during the test. Next, the maximum load (N) and area under the curve (mJ) were calculated as the area of ​​the polymer in the overlapping region (cm 2 ) which is the apparent shear strength (N / cm 2 ) and apparent AUC (mJ / cm 2 ) Repeated at least four times. Mean values ​​and standard deviations were calculated.

[0085] The results are shown in Table 3. [Table 3]

Claims

1. 1. A composition comprising a prepolymer having activated groups and activated and functionalized groups on a polymer backbone, having a zeta potential in the range of 0 to 45 mV; the polymer backbone of the prepolymer is of the formula (-A-B-) n ; A is derived from a substituted or unsubstituted polyol, B is derived from a substituted or unsubstituted polyacid, n is greater than 1, The activated and functionalized group can be obtained by reacting the activated group with a compound containing a charged or chargeable nitrogen atom, as represented by formula (IV): 【Chemistry 1】 (IV) and In the formula, R a , R b , R c , R d , R e and R f is independently selected from H, alkyl, alkenyl, and aryl, and n represents an integer of 1 or greater.

2. 2. The composition of claim 1, wherein the zeta potential is in the range of 5 to 40 mV.

3. 3. The composition of claim 2, wherein the zeta potential is in the range of 5 to 30 mV.

4. 4. The composition according to claim 1, wherein the ratio of the activated and functionalized groups containing a charged nitrogen atom is between 0.05 and 0.4 moles per mole of monomer unit relative to the number of monomer units in the main chain.

5. 2. The composition of claim 1, wherein the polyol is a triol and B is a diacid selected from the group consisting of glutaric acid, adipic acid, pimelic acid, sebacic acid, and azelaic acid.

6. 6. The composition of claim 5, wherein said polyol is glycerol or trimethylolpropane ethoxylate and said B is sebacic acid.

7. The composition of claim 1 wherein said polyol is a diol and said B is a triacid.

8. 8. The composition of claim 7, wherein said polyol is octanediol and said B is citric acid.

9. The prepolymer has the formula (VIII): 【Chemistry 2】 (VIII) and wherein p, q, and r are integers from 1 to 20, n, m, and o are integers greater than 1, and R a , R b , R c , R d , R e and R f The composition of any one of claims 1 to 6, wherein is independently selected from H, alkyl, alkenyl, and aryl.

10. The composition of any one of claims 1 to 9, further comprising an initiator.

11. the initiator is a redox composition, the redox composition comprising: 0.1 to 5 wt % of a reducing agent selected from the group consisting of 4-N,N-trimethylaniline, N,N-bis(2-hydroxyethyl)-p-toluidine, N,N-dimethylaniline, N,N-diethylaniline, sodium p-toluenesulfonate, and N-methyl-N-(2-hydroxyethyl)-p-toluidine; 0 to 5 wt % of an oxygen inhibitor selected from the group consisting of 4-(diphenylphosphino)styrene and triphenylphosphine; 0.005 to 0.5 wt % of a working time agent selected from the group consisting of Tempol and 4-methoxyphenol; and 11. The composition of claim 10, comprising 0.1 to 10 wt % of an oxidizing agent selected from the group consisting of ammonium persulfate, potassium persulfate, and benzoyl peroxide.

12. The composition of claim 10 wherein the initiator is a photoinitiator.

13. The photoinitiator may be 2-dimethoxy-2-phenyl-acetophenone, 2-hydroxy-1-[4-(hydroxyethoxy)phenyl]-2-methyl-1-propanone, 1-hydroxycyclohexyl-1-phenyl ketone, 2-hydroxy-2-methyl-1-phenyl-1-propanone, 2-benzyl-2-(dimethylamino)-1-[4-morpholinyl)phenyl]-1-butanone, methyl benzoylformate, oxy-phenyl-acetic acid-2-[2-oxo-2-phenyl-acetoxy-ethoxy]-ethyl ester, 2-methyl-1-[4-(methylthio) 13. The composition of claim 12, wherein the phenylbis(2,4,6-trimethylbenzoyl)phosphine oxide is selected from the group consisting of phenyl]-2-(4-morpholinyl)-1-propanone, diphenyl(2,4,6-trimethylbenzoyl)-phosphine oxide, phenylbis(2,4,6-trimethylbenzoyl)phosphine oxide, and combinations thereof.

14. A method for preparing a composition according to any one of claims 1 to 13, comprising the steps of: i) a monomer polymerization step to provide a prepolymer backbone; ii) activation of the backbone monomer units to provide an activated prepolymer; and iii) functionalizing the activated prepolymer with a compound containing a charged or chargeable nitrogen atom to provide an activated and functionalized prepolymer. Including, The method, wherein the monomers providing the polymer backbone include a diol or triol and a diacid or triacid.

15. the activation in step ii) is achieved by acrylation of a hydroxy group to give an acrylate group; and / or 15. The method of claim 14, wherein the functionalization in step iii) is achieved by reaction of the acrylate group with an amine to give an amine group, and acidification of the resulting amine to give an ammonium group.

16. 16. The method of claim 15, wherein the acrylation is accomplished by reaction with an acrylic isocyanate or the amine is selected from the group consisting of diethylamine, triethylamine, diisopropylethylamine, dibutylamine, and piperidine.

17. A method for hardening the composition of any one of claims 1 to 13, comprising hardening the composition by stimulation.

18. A composition according to any one of claims 1 to 13 for use in a method for adhering or sealing tissue or for adhering tissue to the surface of a medical device.

19. A cured composition obtained by curing the composition according to any one of claims 1 to 13.

20. 20. A molded article comprising the cured composition of claim 19.

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