Compositions comprising an activated and functionalized prepolymer

Abstract

Compositions are disclosed that comprise a prepolymer having an activated and functionalized group on a polymer backbone. The compositions can be used in methods for adhering or sealing tissue or for adhering a medical device to the surface of tissue.

Description

Field of the Invention

[0001] The present invention relates to compositions comprising activated and functionalized prepolymers, methods of making the compositions, methods of curing the compositions, cured compositions obtainable therefrom, uses of the compositions, and methods of using the compositions. Background of the Invention

[0003] Open-heart surgery typically relies on suture-based closure or connection of cardiovascular structures. However, this can be technically challenging due to the fragility of young infant tissue and diseased or damaged adult tissue, leading to longer operative times, an increased risk of bleeding or dehiscence complications, and thus worse outcomes. In addition, cardiopulmonary bypass (CPB) is required for open-heart surgery, and this has significant side effects, including inflammatory responses and potential neurological complications.

[0004] Although recently there have been catheter-based interventions for closing cardiac defects such as atrial and ventricular septal defects (ASDs and VSDs) in an effort to reduce the invasiveness of surgery, there remain significant challenges in fixing devices within the beating heart. Specifically, fixation of devices for catheter-based closure of cardiac septal defects currently relies on mechanical devices that grip tissue. This can cause damage to critical structures such as heart valves or specialized conduction tissue. In addition, if there are inappropriate tissue margins around the defect, the prosthesis may shift, damaging adjacent structures and also leaving a residual defect, limiting device application. Thus, this approach can only be applied to selected patients depending on the anatomical location and geometry of the defect.

[0005] Fast-curing soft and conformable tissue adhesives can be used to join tissue surfaces together or to attach a prosthetic device to tissue without the need for mechanical clamping or fixation, thereby avoiding tissue compression and erosion. Such materials can find wide applications not only in minimally invasive cardiac repair but also in soft tissue repair potentially with minimal scarring and damage. For example, in vascular surgery, suture-based anastomoses do not always produce an immediate hemostatic seal and can create irregularities in the endothelium that are prone to thrombus formation. In addition, the presence of permanent sutures can cause a foreign body reaction at the repair site as well as further inflammation and scarring, which may increase the risk of late vascular occlusion. Tissue adhesives can accomplish such repairs with an immediate seal and minimal scarring or tissue damage.

[0006] Currently available clinical adhesives, such as medical-grade cyanoacrylate (CA) or fibrin sealants, are easily washed off or cured under dynamic wet conditions, are toxic and cannot be used internally, and / or exhibit weak adhesive properties, making them unable to withstand the forces inside the ventricles and large blood vessels. In addition, many of these adhesives exhibit activation properties, which make fine adjustment or repositioning of the device very difficult. Moreover, many adhesives under development achieve tissue adhesion only through chemical reactions with functional groups on the tissue surface and thus become ineffective in the presence of blood.

[0007] Alternatives to cyanoacrylate have been explored. US 8,143,042 B2 describes biodegradable elastomers prepared by crosslinking a prepolymer containing crosslinkable functional groups such as acrylate groups. It also discloses the desirability of increasing the number of free hydroxyl groups in the polymer in order to increase the viscosity of the polymer. Increasing the number of hydroxyl groups in the main chain also results in enhanced solubility in physiological fluids. This suggests that the main mechanism of polymer adhesion is the chemical interaction between functional groups such as the free hydroxyl groups of the polymer and the tissue to which it is applied. However, this type of chemical interaction becomes ineffective in the presence of body fluids, particularly blood, as shown in Artzi et al., Adv. Mater. 21, 3399 - 3403 (2009).

[0008] Similarly, Mahdavi et al., 2008, PNAS, 2307 - 2312 describe nanoscale patterned elastomeric polymers and propose the application of a thin layer of oxidized dextran (DXTA) with aldehyde functional groups to increase the adhesive strength of the adhesive by promoting covalent crosslinking between the terminal aldehyde groups in DXTA and the amine groups in tissue proteins. This adhesion mechanism, which is essentially based on covalent bonding between free radicals generated during the curing process and the functional groups of the tissue, has several limitations. Using adhesives with reactive chemistry requires drying the tissue surface before applying the prepolymer, which makes it very challenging to use in cardiac applications, such as during emergency surgery. Additionally, reactive chemistry can denature proteins or tissues and promote unwanted immune responses, such as local inflammation that can lead to adhesion rejection. Moreover, reactive chemistry that bonds only to the tissue surface may have lower adhesion because the interface will be more distinct and thus there will be a mismatch in mechanical properties at the interface between the glue and the tissue.

[0009] Elastomeric crosslinked polyesters are disclosed in US2013 / 0231412 A1. Biodegradable polymers are disclosed in US 7,722,894 B2. Adhesive articles are disclosed in W02009067482A1 and W02014 / 190302A1. A blood-resistant surgical glue is described in Lang et al., “A Blood-Resistant Surgical Glue for Minimally Invasive Repair of Vessels and Heart Defects,” Sci. Transl. Med., January 8, 2014: Vol. 6, No. 218, p. 218ra6 and WO2014 / 190302A1. SUMMARY OF THE INVENTION

[0011] The present invention provides improved and commercially viable activated and functionalized prepolymers that can be easily applied to a desired location, are biocompatible (non-toxic), and exhibit strong adhesion once cured / crosslinked, resulting in improved tissue sealants / adhesives.

[0012] The improved activated and functionalized prepolymers remain in the desired location before curing / crosslinking, even in the presence of body fluids such as blood.

[0013] The improved activated and functionalized prepolymers are stable when stored.

[0014] More specifically, the present invention provides a composition comprising:

[0015] A prepolymer having activated and functionalized groups on the polymer backbone, wherein the zeta potential of the composition is in the range of 0 - 45 mV.

[0016] The present invention also provides a method for preparing the composition of the present invention.

[0017] The present invention also provides a method for curing the composition according to the present invention, comprising curing the composition with a stimulant such as light in the presence of a photoinitiator.

[0018] The present invention also provides a cured composition obtainable by the curing method according to the present invention. The cured composition is desirably an adhesive, i.e., an adhesive that can strongly bind to a surface or can bind surfaces to each other.

[0019] The present invention also provides a method of using the composition according to the present invention and uses of the composition according to the present invention for gluing or sealing tissue or for adhering a medical device to a tissue surface.

[0020] The inventors have found that the present invention provides advantages not found in the prior art compared to known compositions.

[0021] Brief Description of the Drawings

[0022] Figure 1 A graph showing the zeta potential of the composition according to the invention and the adhesion of the composition after curing.

[0023] Figures 2 - 8 Showing the synthesis of the composition according to the invention. Detailed Description of the Invention

[0025] Prepolymer

[0026] Preferably, the polymer backbone of the prepolymer comprises polymer units having the general formula (-A-B-) n wherein A is derived from a substituted or unsubstituted polyol or mixtures thereof and B is derived from a substituted or unsubstituted polyacid or mixtures thereof; and n represents an integer greater than 1. The polymer backbone is composed of repeating monomer units having the general formula -A-B-.

[0027] The term "substituted" has its usual meaning in chemical nomenclature and is used to describe compounds in which a hydrogen on the main carbon chain has been replaced by a substituent such as an alkyl group, an aryl group, a carboxylic acid, an ester, an amide, an amine, a carbamate, an ether or a carbonyl group.

[0028] Component A of the prepolymer can be derived from polyols or mixtures thereof, such as diols, triols, tetraols or higher. Suitable polyols include diols such as alkane diols, preferably octanediol; triols such as glycerol, trimethylolpropane, trimethylolpropane ethoxylate, triethanolamine; tetraols such as erythritol, pentaerythritol; and higher polyols such as sorbitol. Component A can also be derived from unsaturated polyols such as tetradeca-2,12-diene-1,14-diol, polybutadiene diol or other polyols can also be used, including macromonomer polyols such as polyethylene oxide, polycaprolactone triol and N-methyldiethanolamine (MDEA). Preferably, the polyol is a substituted or unsubstituted glycerol.

[0029] Component B of the prepolymer is derived from polyacids or mixtures thereof, preferably diacids or triacids. 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 diacids having greater than 10, greater than 15, greater than 20 and greater than 25 carbon atoms. Non-aliphatic diacids can 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 a substituted or unsubstituted sebacic acid.

[0030] The polyol-based polymers described in US2011 / 0008277, US 7,722,894 and US 8,143,042, the contents of which are incorporated herein by reference, are suitable polymer backbones for use in the present invention.

[0031] 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 can also include 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 the biological properties. Aromatic groups, aliphatic groups, and halogen atoms can be used to modify the intermolecular interactions within the polymer.

[0032] Alternatively, the polymer backbone of the prepolymer is a polyamide or polyurethane backbone. For example, polyamines (containing two or more amino groups) can be used to react with polyacids and polyols or with polyacids after reacting with polyols. 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 other instances, polyisocyanates (containing two or more isocyanate groups) can be used to react with polyacids and polyols or with polyacids after reacting with polyols. Exemplary polyester polyurethanes include those described in US 2013 / 231412.

[0033] The weight average molecular weight (Mw) of the prepolymer, measured by gel permeation chromatography equipped with a refractive index detector, can 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 can 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 can be from about 1,000 daltons to about 10,000 daltons, from about 2,000 daltons to about 10,000 daltons, from about 3,000 daltons to about 10,000 daltons, from about 5,000 daltons to about 10,000 daltons. Preferably, it is about 4,500 daltons.

[0034] As used herein, the term "about" means within 10% of a given value or range, preferably within 8%, and more preferably within 5%. According to a particular embodiment, "about X" means X when X refers to a value or range.

[0035] The prepolymer can have a polydispersity 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, measured by gel permeation chromatography equipped with refractive index. Preferably, it is about 2.5.

[0036] The molar ratio of polyol to polyacid in the prepolymer 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.

[0037] Activated prepolymer

[0038] The prepolymer in the composition of the present invention has an activating group on its polymer backbone.

[0039] The activating group is a functional group that can react or has reacted to form a crosslink. The prepolymer is activated as follows: one or more functional groups on the monomer units of the backbone are reacted to provide one or more functional groups that can react or have reacted to form a crosslink, thereby producing a cured polymer. According to an embodiment, the prepolymer has activating groups with different properties on its backbone monomer units. The polymer backbone of the prepolymer can comprise polymer units having the general formula (-A-B-) 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.

[0040] Suitable functional groups to be activated on the prepolymer backbone include hydroxyl groups, carboxylic acid groups, amines and combinations thereof, preferably hydroxyl and / or carboxylic acid. The free hydroxyl or carboxylic acid groups on the prepolymer can be activated by functionalizing the hydroxyl with a structural moiety that can form a crosslink between polymer chains. The activated group can be a free hydroxyl or carboxyl group on the A and / or B structural moieties in the prepolymer.

[0041] The free hydroxyl or carboxyl can be functionalized with various functional groups such as vinyl groups. The vinyl groups can be introduced by various techniques known in the art such as by vinylation or acrylation. According to the present invention, the vinyl group contains the following structure -CR x =CR y R z wherein R x 、R y 、R z are independent of each other and are selected from the following: H, alkyl such as methyl or ethyl, aryl such as phenyl, substituted alkyl, substituted aryl, carboxylic acid, ester, amide, amine, carbamate, ether and carbonyl.

[0042] Preferably, the activating group is or contains an acrylate group. According to the present invention, the acrylate group can contain the following group: -C(=O)-CR p=CR q R r , wherein R p 、R q 、R r are independent of each other and are selected from the following: H, alkyl such as methyl or ethyl, aryl such as phenyl, substituted alkyl, substituted aryl, carboxylic acid, ester, amide, amine, carbamate, ether and carbonyl. According to an embodiment, the activated prepolymer contains a mixture of different acrylate groups.

[0043] Preferably, all or part of the acrylate groups containing -C(=O)-CR p =CR q R r groups are such that R p 、R q and R r are H, or R p is CH3, R q and R r are H, or R p and R q are H and R r is CH3, or R p and R q are H and R r is phenyl.

[0044] The free carboxyl groups on the prepolymer can also be used to incorporate vinyl groups into the main chain of the prepolymer. For example, 2-hydroxyethyl methacrylate can be incorporated chemically by activation using carbonyldiimidazole through the COOH groups of the prepolymer.

[0045] In an embodiment of the present invention, at least a portion of the activating groups on the polymer backbone of the prepolymer can be olefin groups (such as acrylate, methacrylate). Suitably, techniques such as 1 H NMR are used to measure the degree of activation (such as acrylation). The degree of activation (such as acrylation) is suitably characterized as "DA". The proportion of activating groups can be compared to the number of monomer units in the main chain. This can vary and can be 0.1 - 0.8 mol / mol monomer unit, preferably 0.2 - 0.6 mol / mol monomer unit and most preferably 0.3 - 0.45 mol / mol monomer unit, for example 0.3 mol / mol monomer unit, to achieve optimal burst performance properties at room temperature or elevated temperatures up to 40 °C, preferably 37 °C. Most preferably, when the degree of activation is as described above and the reactive functional group is acrylate, i.e., the degree of acrylation as above. When the polymer units of the main chain have the general formula (-A-B-) nWhen A is derived from a substituted or unsubstituted polyol and B is derived from a substituted or unsubstituted polyacid, the ratio of the monomer units having the general formula -A-B- and the activating groups can be described as per mole of polyacid or per mole of polyol. The DA range described above is preferably mol / mol of polyacid.

[0046] The prepolymer in the composition of the present invention is preferably derived from an activated prepolymer having the general formula (I):

[0047]

[0048] wherein n and p each independently represent an integer equal to or greater than 1, and wherein R2 in each single unit represents hydrogen or a polymer chain or -C(=O)-CR3=CR4R5 or C(=O)NR6-CR7R8-CR9R 10 -O-C(=O)-CR3=CR4R5, wherein R3, R4, R5, R6, R7, R8, R9 and R 10 are independent of each other and are selected from the following: H, alkyl such as methyl or ethyl, aryl such as phenyl, substituted alkyl, substituted aryl, carboxylic acid, ester, amide, amine, carbamate, ether and carbonyl.

[0049] Preferably, R3, R4 and R5 are H; or R3 is CH3, 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 10 are H.

[0050] Preferably, p is an integer of 1-20, more preferably 2-10, even more preferably 4-10. Most preferably, when p = 8.

[0051] Preferably, the prepolymer in the composition of the present invention is derived from an activated prepolymer containing monomer units having the general formula (II):

[0052]

[0053] wherein n represents an integer equal to or greater than 1.

[0054] More preferably, the prepolymer in the composition of the present invention is derived from an activated prepolymer having monomer units with the general formula (II):

[0055]

[0056] wherein n represents an integer equal to or greater than 1.

[0057] In addition to acrylates or other vinyl groups, other reagents can be used to provide activating groups on the prepolymer backbone. Examples of such reagents include, but are not limited to, glycidyl, epichlorohydrin, triphenylphosphine, diethyl azodicarboxylate (DEAD), diaziridine, divinyl adipate, and divinyl sebacate, using enzymes as catalysts, phosgene-type reagents, diacyl chlorides, dianhydrides, dihalides, metal surfaces, and combinations thereof. The reagents can also include isocyanates, aldehydes, epoxy groups, vinyl ethers, thiols, DOPA residues, or N-hydroxysuccinimide functional groups.

[0058] Zeta potential - activated and functionalized prepolymer

[0059] The inventors have found a positive correlation between the zeta potential of the composition and the adhesion strength of the composition after curing. The zeta potential of the compositions of the present invention can vary based on the prepolymer used (including the compositional makeup of the prepolymer).

[0060] "Zeta potential" refers to the charge generated at the interface between a solid surface and its liquid medium, measured in millivolts (mV) or volts (V). It is the potential difference formed between the dispersion medium and the fixed layer of the fluid of the dispersed particles attached to the interface double layer. The magnitude of the zeta potential indicates the degree of electrostatic repulsion between adjacent similarly charged particles in the dispersion.

[0061] The zeta potential of the composition will be affected by the number and nature of the charged atoms in the prepolymer, but will also be affected by other charged substances that may be present in the composition.

[0062] Thus, the prepolymers of the present invention are not only activated by introducing functional groups capable of forming crosslinks, preferably acrylate groups, but they are also functionalized with charged atoms.

[0063] In a preferred embodiment of the present invention, at least a portion of the activating groups (e.g., acrylates) on the polymer backbone of the prepolymer have reacted with a compound containing a charged or chargeable atom, preferably a charged heteroatom, and even more preferably a positively charged heteroatom. Hereinafter, they are referred to as "activated functional groups".

[0064] In addition, at least a portion of the other groups (e.g., hydroxyl or carboxyl groups) on the polymer backbone of the prepolymer can include a charged heteroatom, preferably a positively charged heteroatom.

[0065] The positively charged heteroatoms on the prepolymer can 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.

[0066] In the composition according to the invention, the ratio of the activated functional groups (i.e., such activated groups which have been modified such that they contain charged atoms, preferably charged heteroatoms, even more preferably positively charged heteroatoms) to the number of monomer units in the main chain can vary according to the polymer and can suitably range from about 0.05 - about 0.4 mol / mol monomer unit, preferably from about 0.09 - about 0.25 mol / mol monomer unit. Suitably, the ratio of the activated functional groups is measured by techniques such as 1 1H NMR. When the polymer units of the main chain have the general formula (-A-B-) 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 -A-B- and the ratio of the activated functional groups can be described per mole of polyacid or per mole of polyol. The ranges described above are preferably mol / mol polyacid. When the functional groups (including the activated functional groups) on the main chain monomers of the prepolymer containing positively charged heteroatoms are positively charged nitrogen atoms, then the ratio of the functional groups containing positively charged heteroatoms is suitably characterized as "DN+". This is the number of positively charged nitrogen atoms compared to the number of monomer units in the main chain. Using 1 1H NMR spectroscopy, the DN+ parameter is suitably determined using the characteristic peak of the hydrogen atom located on the positively charged nitrogen atom. The DN+ parameter is suitably described as mol / mol polyacid.

[0067] The activated functional groups containing positively charged nitrogen atoms preferably have the general formula (III):

[0068]

[0069] where R a , R b , R c , R d , R e and R f are independently selected from H, alkyl, alkenyl and aryl. Preferably, at least one of R d , R e and R f is H.

[0070] R a , R b , R c , R d , R e and R fThe alkyl group is suitably selected from the following: straight-chain alkyl groups (such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.) or branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), or alkyl-substituted cycloalkyl groups. Preferably, any alkyl group is a C 1-8 alkyl group, more preferably a C 1-4 alkyl group and most preferably a methyl or ethyl group.

[0071] R a 、R b 、R c 、R d 、R e and R f The alkenyl groups of R 2-8 are suitably selected from the following: straight-chain alkenyl groups (such as vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.) or 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 a C

[0072] R a 、R b 、R c 、R d 、R e and R f The aryl groups of R

[0073] are suitably selected from the following: 5- and 6-membered monocyclic aromatic groups, as well as polycyclic aryl groups, such as tricyclic or bicyclic (such as naphthalene, anthracene, phenanthrene, etc.). The aryl group can also be fused or bridged with, for example, non-aromatic alicyclic or heterocyclic rings to form, for example, polycycles.

[0073] Preferably, R a is hydrogen. Preferably, R b is hydrogen. Preferably, R c is hydrogen.

[0074] Preferably, one, two, or three of R d 、R e and R f are hydrogen. Most preferably, one of R d 、R e and R f is hydrogen. In another embodiment, R d 、R e and R f are not hydrogen.

[0075] Alternatively, the activated functional group including a positively charged nitrogen atom preferably has the general formula (IV):

[0076]

[0077] wherein R a , R b , R c , R d , R e and R f are defined as the groups of formula (III) above, and n represents an integer equal to or greater than 1, preferably 1 - 4.

[0078] According to a preferred embodiment, the activated functional group of general formula (IV) is:

[0079]

[0080] According to another embodiment, the positively charged heteroatom is phosphorus or sulfur. Examples of activated functional groups including a positively charged sulfur atom or a positively charged phosphorus atom may have the general formula (V) or (VI):

[0081]

[0082] wherein R a , R b , R c , R d , R e and R f are defined as the groups of formula (III) above.

[0083] When, in a preferred embodiment, a charged atom of the prepolymer is present on the activating (e.g., acrylated) group of the main chain, the charged atom may also be present on the main chain, for example, as a substitution of a polyol group of a polyacid, present on the hydroxyl group of a carboxyl group.

[0084] In one embodiment of the present invention, the prepolymer has the general formula (VII):

[0085]

[0086] where p is between 1 and 20; wherein n, m, and o are integers greater than 1, and wherein R a , R b , R c , R d , R e and R f are defined as the groups of formula (III) above.

[0087] p is preferably 2 - 10, more preferably 4 - 10, and most preferably p = 8.

[0088] n, m, and o are integers greater than 1. The values of n, m, and o are suitably large enough such 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.

[0089] For the prepolymer according to general formula (VII), some of the hydroxyl groups on the main-chain monomer units are activated with acrylate groups and some are activated functional groups including charged heteroatoms (including positively charged nitrogen atoms). The preferred ratio of n:m:o will be determined by the preferred amounts of the activating groups and the activated functional groups.

[0090] In another embodiment of the present invention, the prepolymer has the general formula (VIII):

[0091]

[0092] where p, q, and r are integers between 1 and 20; where n, m, and o are integers greater than 1, and where R a 、R b 、R c 、R d 、R e and R f are defined as the groups with respect to formula (III) above.

[0093] p is preferably 2 - 10, more preferably 4 - 10, and most preferably p = 8. q is preferably 1 - 4, most preferably q is 2. r is preferably 1 - 4, most preferably r is 2.

[0094] n, m, and o are integers greater than 1. The values of n, m, and o are suitably large enough such 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.

[0095] For the prepolymer according to general formula (VIII), some of the hydroxyl groups on the main-chain monomer units are activated with acrylate groups and some are activated functional groups including charged heteroatoms (including positively charged nitrogen atoms). The preferred ratio of n:m:o will be determined by the preferred amounts of the activating groups and the activated functional groups.

[0096] Zeta potential measurement

[0097] For the composition of the present invention, the following protocol can be used to measure the zeta potential:

[0098] The instrument used to measure the zeta potential is a Zetasizer Nano-ZS Zen 3600. A zeta potential cell DTS1070 from Malvern is used.

[0099] A standard solution was prepared by weighing 15 mg of the prepolymer in a glass bottle. 50 μL of isopropanol and 1 mL of deionized water were added. The solution was subjected to vortexing to achieve complete dissolution of the prepolymer. 50 μL of the resulting solution was transferred to a 20 mL glass bottle and 5 mL of deionized water was added.

[0100] 1 mL of the solution was added to the zeta potential cell and the cell was placed in a Zetasizer instrument. The instrument was set to "Manual" and then "Measurement type - zeta potential sample" using the following selections: Material - polystyrene latex, Dispersant - water, General options - Smoluchowski mode, Temperature - 37 °C, Equilibration time - 120 s, Cell - disposable folded capillary cell.

[0101] Three measurements were made using the automatic mode with a minimum of 10 runs and a maximum of 100 runs. Each sample was run 3 times with zero delay between measurements.

[0102] In the composition according to the invention, the zeta potential (as measured according to the above-described protocol) is between 0 and about 45 mV, preferably between about 5 and 40 mV, more preferably between about 5 and 30 mV.

[0103] Composition

[0104] The composition according to the invention can be manufactured in the presence of a colorant and / or the composition according to the invention can be mixed with a colorant. Preferred examples of colorants are those recommended by the FDA for use in medical devices, pharmaceuticals or cosmetics.

[0105] Similarly, the composition can also contain stabilizers such as MEHQ or N-phenyl-2-naphthylamine (PBN).

[0106] The activated and functionalized prepolymers of the composition can also react with one or more additional materials to modify the crosslinking between polymer chains. For example, before or during curing / crosslinking, one or more hydrogels or other oligomers or monomers or polymer precursors (such as precursors that can be modified to contain acrylate groups) such as poly(ethylene glycol), dextran, chitosan, hyaluronic acid, alginate, other acrylate-based precursors, including for example acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, methyl acrylate, ethyl acrylate, acrylonitrile, n-butanol, methyl methacrylate, acrylic anhydride, methacrylic anhydride and TMPTA, trimethylolpropane trimethacrylate, pentaerythritol trimethacrylate, pentaerythritol tetramethacrylate, ethylene glycol dimethacrylate, dipentaerythritol pentacrylate, bis-GMA (bisphenol A glycidyl methacrylate) and TEGDMA (triethylene glycol dimethacrylate), sucrose acrylate; other thiol-based precursors (monomers or polymers); other epoxy-based precursors; and combinations thereof, can react with the acrylated prepolymer.

[0107] The composition according to the present invention can be a surgical composition and is suitable for use as a tissue sealant and / or adhesive. The composition is suitable to have flow properties such that it can be applied to a desired area through a syringe or catheter, but is sticky enough to remain at the application site and not be washed away by body fluids such as water and / or blood.

[0108] Preferably, the viscosity of the composition is from 500 to 100,000 cP, more preferably from 1,000 to 50,000 cP, even more preferably from 2,000 to 40,000 cP and most preferably from 2,500 to 25,000 cP. Viscosity analysis is carried out using a Brookfield DV-II+Pro viscometer with a 2.2 mL chamber and an SC4-14 rotor, with the speed varying from 5 to 80 rpm during the analysis. The viscosities mentioned above exist in the relevant temperature range for medical applications, i.e., from room temperature up to 40 °C, preferably 37 °C.

[0109] The composition of the present invention can be incubated in body fluids such as blood before administration and curing, without a significant reduction in the adhesion strength upon curing.

[0110] The composition of the present invention is suitably stable in body fluids such as blood. More particularly, in the absence of deliberately applied stimulants such as light, such as UV light, heat or chemical initiators to initiate crosslinking, the composition of the present invention does not suitably crosslink spontaneously in body fluids.

[0111] The composition can be cured using free radical initiation reactions such as photoinitiated polymerization, thermally initiated polymerization and redox-initiated polymerization.

[0112] Preferably, the composition is irradiated with light, such as ultraviolet (UV) light, in the presence of a photoinitiator to facilitate the reaction. Examples of suitable photoinitiators include, but are not limited to: 2-dimethoxy-2-phenyl-acetophenone, 2-hydroxy-1-[4-(hydroxyethoxy)phenyl]-2-methyl-1-propanone (Irgacure 2959), 1-hydroxycyclohexyl-1-phenylketone (Irgacure 184), 2-hydroxy-2-methyl-1-phenyl-1-propanone (Darocur 1173), 2-benzyl-2-(dimethylamino)-1-[4-(morpholinyl)phenyl]-1-butanone (Irgacure 369), methyl benzoylformate (Darocur MBF), 2-[2-oxo-2-phenyl-acetoxy-ethoxy]-ethyl 2-oxo-2-phenyl-acetate (Irgacure 754), 2-methyl-1-[4-(methylthio)phenyl]-2-(4-morpholinyl)-1-propanone (Irgacure 907), diphenyl(2,4,6-trimethylbenzoyl)-phosphine oxide (Darocur TPO), phosphine oxide, phenylbis(2,4,6-trimethylbenzoyl) (Irgacure 819), and combinations thereof.

[0113] Preferably, the composition is irradiated with visible light (usually blue or green light) in the presence of a photoinitiator to facilitate the reaction. Examples of visible light photoinitiators include, but are not limited to, diphenyl(2,4,6-trimethylbenzoyl)-phosphine oxide, eosin Y disodium salt, N-vinyl-2-pyrrolidone (NVP), and triethanolamine and camphorquinone.

[0114] In applications of compositions involving in vivo photopolymerization and other medical applications, it is preferred and required by regulatory authorities to use a cell-compatible photoinitiator. The photoinitiator Irgacure 2959 can be used, which causes minimal cytotoxicity (cell death) in a wide range of mammalian cell types and species.

[0115] For photopolymerization to occur, the composition (and the substrate to which the composition is applied, if applicable) is preferably sufficiently transparent to light.

[0116] In applications of curing polymers in vivo, it is preferred to control the temperature at which curing occurs so as not to damage the tissue to which the composition has been applied. Preferably, during irradiation, the composition is not heated to above 45 °C, more preferably not above 37 °C, and even more preferably not above 25 °C.

[0117] In addition to photocrosslinking, the composition can also be thermally cured by Mitsunobu-type reactions, polymerization initiated by redox pairs such as benzoyl peroxide, N,N-dimethyl-p-toluidine, ammonium persulfate or tetramethylethylenediamine (TEMED), and Michael-type addition reactions using bifunctional mercapto compounds.

[0118] In one embodiment, a redox composition (i.e., a composition that can be thermally cured by free radical polymerization initiated by a redox pair) can contain 0.1 to 5 wt% of a reducing agent such as 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 initiator such as 4-(diphenylphosphino)styrene or triphenylphosphine; 0.005 to 0.5 wt% of a working reagent such as Tempol or 4-methoxyphenol; and 0.1 to 10 wt% of an oxidizing agent such as ammonium persulfate, potassium persulfate or benzoyl peroxide. The initiation of the reaction of the redox pair to initiate polymerization is affected by the absolute and relative amounts of the different reagents.

[0119] Upon polymerization, the activated and functionalized prepolymer forms a crosslinked network with improved adhesion properties and exhibits significant adhesion strength even in the presence of blood and other body fluids. The cured polymer obtained after curing is preferably elastic enough to resist movement of the underlying tissue such as the contraction of the heart and blood vessels. The adhesive can provide a seal to prevent leakage of fluids or gases. The adhesive is preferably biodegradable and biocompatible, thereby causing a minimal inflammatory response. The adhesive is preferably elastomeric.

[0120] Biodegradability can be evaluated in vitro, for example, in phosphate buffered saline (PBS) or under acidic or basic conditions. Biodegradability can also be evaluated in vivo, for example, in animals such as mice, rats, dogs, pigs or humans. The degradation rate can be evaluated by measuring the loss of polymer mass over time in vitro or in vivo.

[0121] The cured composition, alone or coated on a patch or tissue, suitably exhibits a 90° peel adhesion strength of at least 0.5 N / cm 2 , preferably at least 1 N / cm 2 and even more preferably at least 2 N / cm 2 , for example 1.5 N / cm 2 to 2 N / cm 2 , but preferably greater than 5 N / cm 2 , for example up to 6 N / cm 2 or 7 N / cm 2or greater. The peel adhesion strength is the adhesion value obtained by attaching an adhesive article or sample to a moist tissue, such as the epicardial surface of vascular or cardiac tissue fixed to a flat substrate, such as a metal substrate (stub). The 90° peel adhesion test determines the maximum vertical force (in a tensiometer) (N. Lang et al., Sci. Transl. Med., 2014, 6, 218ra6) that the surface area can withstand before the adhesive detaches.

[0122] According to a preferred embodiment, the compositions of the present invention cure in light and in the presence of a photoinitiator, and the cured compositions exhibit a 90° peel adhesion strength of at least 0.5 N / cm 2 , preferably at least 1 N / cm 2 and even more preferably at least 2 N / cm 2 , for example 1.5 N / cm 2 to 2 N / cm 2 but preferably greater than 5 N / cm 2 , for example up to 6 N / cm 2 or 7 N / cm 2 or greater.

[0123] The cured compositions may also desirably exhibit a burst pressure greater than 100 mmHg, preferably in the range of 400 mmHg to 600 mmHg or greater, for example 400 mmHg or 500 mmHg. The burst pressure or strength is the pressure value obtained by rupturing an explanted porcine carotid artery vessel whose incision is coated with the composition.

[0124] The compositions of the present invention, when cured in light and in the presence of a photoinitiator, preferably have one or more of the following properties:

[0125] i) 90° peel strength greater than 0.5 N / cm 2 , preferably 2 to 7 N / cm 2 or greater; and

[0126] ii) burst performance greater than 100 mmHg, preferably 200 to 300 mmHg or greater.

[0127] According to a preferred embodiment, the compositions of the present invention are used as adhesives, i.e., capable of strongly binding to a surface or binding surfaces to each other after curing.

[0128] According to an alternative embodiment, the compositions of the present invention are used as sealants, i.e., capable of preventing leakage (e.g., of fluids or gases) after curing by forming a barrier or filling void volumes.

[0129] In addition to the adhesion and sealing of wet biological tissues, the composition can adhere to and seal various hydrophilic or hydrophobic substrates (natural or synthetic), including polyethylene terephthalate, expanded polyethylene terephthalate, polyester, polypropylene, silicone, polyurethane, acrylic materials, fixed tissues (such as pericardium), ceramics, or any combination thereof.

[0130] Preparation method

[0131] The method for preparing the composition of the present invention includes several essential steps, which may include several variants. According to a preferred embodiment, the method includes the following steps:

[0132] i) Polymerizing monomers to provide a prepolymer backbone;

[0133] ii) Activating the backbone monomer units to provide an activated prepolymer; and

[0134] iii) Functionalizing the activated prepolymer with a compound containing a charged or chargeable atom to provide an activated and functionalized prepolymer.

[0135] The monomers are preferably component A (a polyol or a mixture of polyols) and component B (a polyacid or a mixture of polyacids) and are suitably added together in a molar ratio range of 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 and added in a 1:1 molar ratio, there are three hydroxyl groups on glycerol for two carboxyl groups on sebacic acid. Therefore, the additional hydroxyl groups on glycerol as well as the terminal carboxylic acid groups can be used for activation.

[0136] The conditions for step i) may include a temperature range of 100 to 140 °C, preferably 120 to 130 °C, an inert atmosphere, preferably containing nitrogen and under vacuum.

[0137] In a preferred embodiment, hydroxyl or carboxyl groups are present on the prepolymer backbone obtained according to step i).

[0138] The activation in step ii) is suitably achieved by acrylation of the prepolymer backbone.

[0139] In a preferred embodiment, the activation is completed by acrylation of the hydroxyl or carboxyl groups. Carboxyl activation can lead to the formation of an acid anhydride, which can be removed (fully or partially) using ethanol, for example (see, for example, WO2016 / 202984).

[0140] One or more acrylates can be used as the acrylation reagent. The acrylate can contain the following groups: -C(=O)-CR p =CR q R r where R p, R q , R r are independent of each other and are selected from the following: H, alkyl such as methyl or ethyl, aryl such as phenyl, substituted alkyl, substituted aryl, carboxylic acid, ester, amide, amine, carbamate, ether and carbonyl. Preferably, R p is H. Most preferably, the acrylation reagent is acryloyl chloride.

[0141] Step ii) can be carried out in the presence of one or more solvents or catalysts. Examples include dichloromethane (DCM), ethyl acetate (EtOAc), dimethylaminopyridine (DMAP), and triethylamine (TEA), or any combination thereof.

[0142] Several purification steps can be carried out at this stage, preferably water washing steps, 2 - 11 times, preferably 2 to 8 times, and most preferably 8 times.

[0143] Alternatively, the activation in step ii) can be acrylation using an isocyanate acrylate compound. The preferred isocyanate acrylate compound is 2-isocyanatoethyl (meth)acrylate.

[0144] For the functionalization step iii), in a preferred embodiment, an amine moiety is grafted onto the prepolymer backbone and then acidified to form a charged amine.

[0145] The grafting of the amine can be carried out by activating specific substitutions on the hydroxyl, carboxyl, or activated (such as acrylate) groups of the prepolymer.

[0146] According to a preferred embodiment, the acrylate group reacts with the amine to produce a grafted tertiary amine group, and the resulting amine is acidified to produce an ammonium group (see C1.3 in the examples).

[0147] According to another embodiment, the amine is modified to an acid anhydride during the activation step and then alternatively or additionally grafted onto a carboxylic acid (see C1.5 in the examples). In such a case, an amide is formed.

[0148] According to another embodiment, the amine is alternatively or additionally grafted onto a carboxylic acid, and the carboxylic acid is modified (such as by modification to an acid anhydride) to react more readily with a nucleophile, such as any bifunctional molecule bearing an alcohol and an amine group, more preferably diethylethanolamine (see C1.6 in the examples).

[0149] According to the present invention, the amine can be a primary amine, secondary amine, or tertiary amine. Preferred amines include diethylamine.

[0150] The amination step iii) is preferably carried out in a solvent such as dichloromethane.

[0151] The electrification of the amine can be carried out by acidification. The acidification is suitably carried out in the presence of an acid such as a carboxylic acid, examples including formic acid and acetic acid or hydrochloric acid.

[0152] According to a specific embodiment, the activation step ii) and the functionalization step iii) can occur in the same reaction step without the need for acidification.

[0153] At least one additive can be added to the composition obtained in step iii). In a preferred embodiment, the additive is selected from photoinitiators, radical initiators, and dyes.

[0154] According to a preferred embodiment, the method further includes one or more purification steps iv) to ensure the removal of solvents, by-products, impurities, or unreacted products from the composition. These can be carried out by any reaction step, and more than one purification technique can be applied during the preparation of the composition.

[0155] In a preferred embodiment, such a purification step can include washing in an aqueous medium. Phase separation during the water wash can be improved by using a salt dissolved in the aqueous phase (such as an aqueous solution of about 50 - about 500 g / L brine, preferably about 300 g / L of a salt such as sodium chloride). 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.

[0156] According to a preferred embodiment, such a purification step can be carried out either by solvent evaporation or supercritical carbon dioxide extraction.

[0157] Use

[0158] Tissue adhesion and sealing

[0159] The composition according to the present invention can be used for adhering or sealing a target surface, including tissue, graft materials such as PTFE-based grafts, or any combination thereof. The method of adhering or sealing a target surface includes applying the composition to the surface and curing the composition.

[0160] Different from conventional tissue adhesives that are activated during application or simultaneously in the presence of water, or hydrophilic adhesives that are rinsed before curing, the composition according to the present invention can be applied to a wet substrate without activation or displacement. The composition can also be applied to a dry substrate.

[0161] The composition can also be used for adhering tissue to the surface of a medical device. The composition can be used in a medical device, either as part or all of the device, or for adhering the device to tissue. The method of adhering tissue to the surface of a medical device includes applying the composition to the surface of the tissue and / or the medical device and curing the composition. The composition can also be used for connecting tissues, including one or more in vivo tissues.

[0162] The surgical adhesives comprising the inventive composition can also be used for other applications. Examples of applications include stopping bleeding due to, for example, wounds or traumas during surgery, such as after suturing a graft to a blood vessel or after a vascular puncture during endovascular surgery. The adhesive does not need to be removed before the surgeon sutures the wound closed, as it will degrade over time. Other types of wounds that can be treated include, but are not limited to, leaking wounds, wounds that are difficult to close or cannot heal properly through normal physiological mechanisms. The applications can be carried out in vivo or in vitro, for human or veterinary use.

[0163] The composition according to the invention can also be made into a biodegradable stent. The stent can increase the diameter of a blood vessel to improve blood flow through the vessel, but because the stent is biodegradable, the blood vessel diameter can increase while reducing the risk of thrombosis or the stent being covered by scar tissue, which can narrow the blood vessel again. The composition can cover the outer surface of the stent to help adhere the stent to the blood vessel wall in such a way that it causes less damage to the tissue or avoids its displacement in the body. Similarly, the composition can cover the surface of any device that comes into contact with tissue to provide a suitable interface for adhering to the tissue.

[0164] The composition according to the invention can be used in a variety of other applications that require an adhesive or sealant. These include, but are not limited to, air leaks after lung resection; for reducing the time of surgery; for sealing the dura mater; for facilitating laparoscopic surgery; as a biodegradable skin adhesive; as a hernia matrix to prevent or reduce the need for staples or pins; for preventing blood loss; for manipulating organs or tissues during surgery; for fixing a corneal graft in place; for repairing the heart to deliver drugs and / or reduce the dilation of the heart after myocardial infarction; for attaching another material to tissue; for strengthening sutures or staples; for distributing force in tissue; for preventing leaks; as a barrier film on the skin to prevent water evaporation from burned skin; as a patch for anti-scar or antibacterial drug administration; for attaching a device to tissue; as a tape for attaching a device to a mucosa to fix the device in the oral cavity, such as to hold dentures and oral appliances; as a tape for anchoring soft tissue to bone; for preventing the formation of holes in tissue; and for enhancing / strengthening the mechanical properties of tissue, etc.

[0165] Administration of bioactive molecules

[0166] The described compositions according to the invention may also contain one or more agents, therapeutic agents, prophylactic agents, and / or diagnostic agents that are released during the period when the material acts as a sealant / adhesive. The agent can be, for example, a small molecule agent having a molecular weight less than 2000, 1500, 1000, 750, or 500 daltons, a biomolecule, such as a peptide, protein, enzyme, nucleic acid, polysaccharide, growth factor, cell adhesion sequence, such as an RGD sequence or integrin, an extracellular matrix component, or a combination thereof. Exemplary classes of small molecule agents include, but are not limited to, anti-inflammatory agents, 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 invention.

[0167] Tissue carrier

[0168] The compositions according to the invention can be used to produce tissue carriers by forming shaped articles in vivo to perform mechanical functions. The shaped articles can be produced by various manufacturing techniques known in the art, including 3D printing. Such articles can perform functions, such as holding two tissues together or placing a tissue in a specific position in vivo or in vitro.

[0169] Tissues can be coated with a layer of the material, such as the lumen of a tissue, such as a blood vessel, to prevent restenosis, reclosure, or vasospasm after a vascular intervention.

[0170] The composition can also contain one or more types of cells, such as connective tissue cells, organ cells, muscle cells, nerve cells, and combinations thereof. Optionally, the material is implanted with one or more of tendon cells, fibroblast cells, ligament cells, endothelial cells, lung cells, epithelial cells, smooth muscle cells, cardiomyocytes, skeletal muscle cells, islet cells, nerve cells, hepatocytes, renal cells, bladder cells, urothelial cells, chondrocytes, and osteoblasts. The combination of cells and the material can be used to support tissue repair and regeneration.

[0171] Anti-adhesion barrier

[0172] The compositions described herein according to the invention can be applied to reduce or prevent the formation of adhesions after surgery. For example, the composition can be applied to prevent the adhesion of brain tissue to the skull after brain surgery or implantation of a device to prevent possible adhesions.

[0173] Other applications

[0174] The composition can also be used to coat tools, such as surgical instruments such as forceps or retractors, to enhance the ability of the tool to manipulate objects. The composition can also be used in industrial applications where a biocompatible degradable binder is desirable, such as to reduce the potential toxicity of degradation products, such as in marine applications, such as for underwater use or attachment to the surface of a ship. The composition can also be used to produce shaped articles by various techniques known in the art, including 3D printing. The shaped articles can have micron or nanoscale resolution.

[0175] The present invention will now be illustrated with reference to the following examples, but the invention is in no way limited to the following examples. Examples

[0176] Example 1: Acrylate functionalization (C1.4)

[0177] (i) Synthesis of poly(glycerol sebacate) (PGS.C1.0) :

[0178] 1. Weigh equimolar amounts of glycerol and sebacic acid.

[0179] 2. Set the reaction mixture temperature between 120 and 130 °C until the monomers are completely melted.

[0180] 3. After the reagents are melted, lower the bath or reaction temperature to the target value of 120 °C and start stirring.

[0181] 4. Replace the air in the flask with nitrogen using three vacuum / purge cycles.

[0182] 5. Carry out the reaction for 8 hours.

[0183] 6. Then remove the nitrogen supply and reduce the pressure using a vacuum pump set to a target of 15 mBar.

[0184] The reaction is carried out until the target Mw (about 3,000 Da) and polydispersity (<3) are reached. As confirmed by nuclear magnetic resonance (NMR), the target glycerol:sebacic acid molar ratio is 1:1.

[0185] (ii) / (iii): Activation (acrylation) and functionalization (amination followed by acidification) of PGS

[0186] The following procedure is used to activate the hydroxyl groups on the PGS backbone:

[0187] React PGS (C1.0) with acryloyl chloride (∼0.37 g of acryloyl chloride (AcCl) / 1 g of PGS) in 10% (w / v) dichloromethane (DCM) and triethylamine (∼0.4 g of triethylamine (TEA) / 1 g of PGS). Ethanol capping of acrylated PGS (C1.1) is achieved by reacting with ethanol overnight at a temperature in the range between 30 and 50 °C.

[0188] The resulting prepolymer was purified by washing with water (preferably 8 times) and distilled to obtain the prepolymer poly(glycerol sebacate) acrylate PGSA (C1.2).

[0189] The acrylated PGS was reacted with diethylamine (61 mg of diethylamine (DEA) / 1 g of acrylated PGS) in dichloromethane at 40 °C for 5 hours, thereby providing the aminated and acrylated PGS (prepolymer C1.3).

[0190] The aminated and acrylated PGS was acidified with acetic acid at room temperature for 15 minutes. The product was purified by washing with brine and distillation. Then the organic solution was concentrated to 50% (w / w). Additives (Irgacure TPO photoinitiator and radical initiator MEHQ) were added, and the product was purified by scCO2 extraction.

[0191] Use 1 1H NMR spectroscopy was used to measure the proportion of groups containing positively charged nitrogen atoms (DN+) and the proportion of groups containing acrylate groups (DA). DN+ was 0.18 mol / mol of polyacid and DA was 0.31 mol / mol of polyacid. This final composition containing prepolymer C1.4 is the composition according to the present invention.

[0192] Example 2: Acrylate functionalization (C1.4)

[0193] Synthesis of PGS (C1.0)

[0194] The synthesis of PSG was completed as presented in Example 1.

[0195] Activation and functionalization of PGS - acrylation, amination, and acidification

[0196] The following procedure was used to activate the hydroxyl groups on the PGS backbone:

[0197] PGS was reacted with acryloyl chloride (0.37 g of AcCl / g of PGS) in 10% (w / v) dichloromethane and triethylamine (0.4 g of TEA / 1 g of PGS), thereby providing acrylated PGS. Ethanol capping of acrylated PGS was achieved by reacting with ethanol overnight at a temperature in the range between 30 and 50 °C. The resulting prepolymer (C1.2) was purified by washing with water twice.

[0198] The acrylated PGS was reacted with diethylamine (about 100 mg of DEA / g of PGS) in dichloromethane at 40 °C for 5 hours, thereby providing aminated PGSA (C1.3).

[0199] The aminated PGSA was acidified with acetic acid (2 molar equivalents compared to DEA) at room temperature for 15 minutes. The product was purified by washing with brine and distillation. Use 1The measurement by 1H NMR spectroscopy includes the ratio of the groups containing positively charged nitrogen atoms (DN+) and the ratio of the groups containing acrylate groups (DA). DN+ is 0.21 mol / mol of polyacid and DA is 0.38 mol / mol of polyacid.

[0200] Additives (Irgacure TPO photoinitiator and radical initiator MEHQ) were added, and the product (C1.4) was purified by scCO2 extraction. The final DN+ is 0.21 mol / mol of polyacid and the final DA is 0.29 mol / mol of polyacid (for the composition containing prepolymer C1.4 according to the present invention).

[0201] Example 3: Acrylate functionalization and simultaneous anhydride removal (C1.5)

[0202] Synthesis of PGS (C1.0)

[0203] The synthesis of PSG was completed as presented in Example 1.

[0204] Activation and functionalization of PGS - acrylation, amination, and acidification

[0205] The following procedure was used to activate the hydroxyl groups on the PGS backbone:

[0206] PGS was reacted with acryloyl chloride (0.37 g of AcCl / g of PGS) in 10% (w / v) dichloromethane and triethylamine (0.4 g of TEA / g of PGS), thereby providing acrylated PGS.

[0207] Diethylamine (approximately 170 mg of DEA / g of PGS) replaced the ethanol capping and was directly added to the previous solution and stirred at room temperature for 20 h, thereby providing aminated PGSA and removing the anhydride in one step.

[0208] The aminated PGS was acidified with acetic acid at room temperature for 15 minutes (2 molar equivalents of acetic acid compared to DEA). The product was purified by washing with brine and distillation. Using 1 The measurement by 1H NMR spectroscopy includes the ratio of the groups containing positively charged nitrogen atoms (DN+) and the ratio of the groups containing acrylate groups (DA). DN+ is 0.54 mol / mol of polyacid and DA is 0.20 mol / mol of polyacid. Additives (Irgacure TPO photoinitiator and radical initiator MEHQ) were added, and the product was purified by scCO2 extraction. The final DN+ is 0.20 mol / mol of polyacid and the final DA is 0.39 mol / mol of polyacid (for the composition containing prepolymer C1.5 according to the present invention).

[0209] Example 4: Prepolymer functionalization by anhydride removal (C1.6)

[0210] Synthesis of PGS (C1.0)

[0211] Synthesize the PSG as presented in Example 1.

[0212] Activation and functionalization of PGS - acrylation, modification with N,N - diethylethanolamine, acidification Use the following procedure to activate the hydroxyl groups on the PGS backbone:

[0213] React PGS (C1.0) with acryloyl chloride (~0.37 g of acryloyl chloride (AcCl) / 1 g of PGS) in 10% (w / v) dichloromethane (DCM) and triethylamine (~0.4 g of triethylamine (TEA) / 1 g of PGS), thereby providing acrylated PGS (C1.1).

[0214] Functionalize the activated prepolymer by modifying the resulting anhydride with N,N - diethylethanolamine.

[0215] Add N,N - diethylethanolamine (82 mL) to 450 mL of acrylated PGS (C1.1). Heat the mixture to 40 °C for 24 h. Then purify the mixture by washing with brine and dry and concentrate the organic layer to a 50% (w / w) solution. Then, add acetic acid (70 mL) and stir the mixture for 5 min. Wash the organic layer with brine, dry and concentrate to a 50% (w / w) solution. Add an additive (Irgacure TPO photoinitiator) and purify the batch by solvent evaporation and evaluate the adhesion properties. DA is 0.74 mol / mol polyacid and the final DN+ of the composition containing C1.6 according to the invention cannot be determined.

[0216] Example 5: Prepolymer activation alternatives (C1.9 and C1.10)

[0217] Synthesis of PGS (C1.0)

[0218] The synthesis of poly(glycerol sebacate) is as described in Example 1.

[0219] Activation (acrylation) and functionalization (amination followed by acidification) of PGS

[0220] Use the following procedure to activate the hydroxyl groups on the PGS backbone:

[0221] React PGS (C1.0) with isocyanate acrylate (~0.306 g of isocyanate acrylate / 1 g of PGS) in 20% (w / v) ethyl acetate, thereby providing acrylated PGS (prepolymer C1.9).

[0222] The resulting activated prepolymer was functionalized by reacting with diethylamine (60 mg of diethylamine / 1 g of activated PGS) in ethyl acetate at 55 °C for 5 hours without an intermediate purification step. The functionalized and activated PGS was acidified with acetic acid for 15 minutes at room temperature (add 0.670 mL AcOH / 1 g of C1.9). The product (C1.10) was purified by washing with brine and distillation. Then the organic solution was concentrated to 50% (w / w). Additives (Irgacure TPO photoinitiator and radical initiator MEHQ) were added, and the product was purified by scCO2 extraction.

[0223] Using 1 1H NMR spectroscopy was used to measure the proportion of groups containing a positively charged nitrogen atom (DN+) and the proportion of groups containing acrylate groups (DA). DN+ was 0.19 mol / mol of polyacid and DA was 0.30 mol / mol of polyacid. This final product containing prepolymer C1.10 is a composition according to the invention.

[0224] Example 6: Simultaneous activation and functionalization (C1.7 and C1.8)

[0225] Synthesis of PGS (C1.0)

[0226] The synthesis of PSG was completed as presented in Example 1.

[0227] Simultaneous activation and functionalization of PGS - simultaneous acrylation and amination

[0228] PGS was dissolved in DCM and a base (TEA or DIPEA) was added (1.20 mol of base / 1 mol of glycerol). In a second flask, AcCl was dissolved in DCM (1.15 mol of AcCl / 1 mol of glycerol). The two flasks were rinsed 3 times using a vacuum / nitrogen cycle. The flask containing the AcCl solution was cooled to 0 °C and kept away from light. The PGS + base solution was added dropwise to the AcCl solution over approximately 3 hours.

[0229] Then the solution was brought back to room temperature and left for 1 hour with stirring.

[0230] The solution was washed once with brine, dried over magnesium sulfate and filtered.

[0231] Ethanol capping of acrylated PGS was achieved by reacting with ethanol overnight at a temperature in the range between 30 and 50 °C.

[0232] Additives (Irgacure TPO photoinitiator and radical initiator MEHQ) were added, and the product was purified by scCO2 extraction. Composition C1.7 preferably uses the base triethylamine (TEA). Composition C1.8 preferably uses the base N,N - diisopropylethylamine (DIPEA).

[0233] Example 7: Aminated poly(triethyleneglycol propyl ether - co - sebacate) acrylate (prepolymer C2.1)

[0234] Synthesis of poly(triethyleneglycol propyl ether - co - sebacate) (PTS, prepolymer C2.0)

[0235] PTS is a polymer similar to PGS, except that it is not prepared from sebacic acid and glycerol, but from sebacic acid and trimethylolpropane ethoxylate.

[0236] The following general protocol was initially used to synthesize poly(trimethylolpropane ethoxylate - co - sebacate) (PTS, prepolymer C2.0):

[0237] 1. Weigh equimolar amounts of trimethylolpropane ethoxylate and sebacic acid.

[0238] 2. Set the temperature of the reaction mixture between 120 and 130 °C until the monomers are completely melted.

[0239] 3. After the reagents are melted, lower the bath or reaction temperature to the target value of 120 °C and start stirring.

[0240] 4. Replace the air in the flask with nitrogen using three vacuum / purge cycles.

[0241] 5. Carry out the reaction for 8 hours.

[0242] 6. Then remove the nitrogen supply and reduce the pressure using a vacuum pump set to a target of 15 mBar.

[0243] The reaction is carried out until the target Mw (approx. 8000 Da) and polydispersity (<2.5) are reached. As confirmed by nuclear magnetic resonance (NMR), the target molar ratio of trimethylolpropane ethoxylate:sebacic acid is 1:1.

[0244] Activation and functionalization of PTS - acrylation, amination, and acidification (C2.1 to C2.4)

[0245] React PTS with acryloyl chloride (0.16 g of AcCl / 1 g of PTS) in 10% (w / v) dichloromethane and triethylamine (0.19 g of TEA / 1 g of PTS), thereby providing acrylated PTS (prepolymer C2.1).

[0246] Ethanol capping of acrylated PTSA is achieved by reacting with ethanol overnight at a temperature in the range between 30 and 50 °C.

[0247] Purify the resulting polymer by washing with water and distillation.

[0248] The acrylated PTS was reacted with diethylamine in dichloromethane (0.035 ml of DEA / 1 g of C2.1) at 40 °C for 5 h, thereby providing acrylated and aminated PTS (prepolymer C2.2).

[0249] The resulting prepolymer (0.04 ml of acetic acid / 1 g of C2.2) was acidified at room temperature for 15 min. The resulting prepolymer (prepolymer C2.3) was purified by washing with water, washing with brine, and distillation.

[0250] An additive (Irgacure TPO photoinitiator) was added, and the product was purified by solvent evaporation. The composition containing prepolymer C2.4 is the composition according to the present invention.

[0251] Example 8: Dual activation and functionalization of PGS (C1.11 and C1.12)

[0252] Synthesis of PGS (C1.0)

[0253] The synthesis of PSG was completed as presented in Example 1.

[0254] Activation and functionalization of PGS - amination and acidification after dual acrylation

[0255] The following procedure was used to activate and functionalize the hydroxyl groups on the polymer backbone:

[0256] PGS (C1.0) was reacted with 2-isocyanatoethyl acrylate (0.14 g / g of C1.0) and 2-isocyanatoethyl methacrylate (0.32 g / g of C1.0) in 20% (w / V) ethyl acetate at 70 °C under magnetic stirring for 16 h, resulting in C1.11.

[0257] Then the reaction mixture was cooled to ambient temperature. In a second step, it was heated to 55 °C and diethylamine (0.15 g / g of C1.0) was added. The mixture was stirred at 55 °C for 5 h. The mixture was cooled to ambient temperature and acetic acid (0.18 g / g of C1.0) was added to the mixture and stirred for 5 min. The product was purified by washing with brine, dried over MgSO4 and filtered. The resulting solution was concentrated to 50% (w / w). An additive (Irgacure TPO photoinitiator and radical initiator MEHQ) was added, and the product was purified by scCO2 extraction.

[0258] Use 1 1H NMR spectroscopy was used to measure the proportion of groups containing positively charged nitrogen atoms (DN+) and the proportion of groups containing methacrylate groups (DA). DN+ was 0.18 mol / mol of polyacid and DA was 0.44 mol / mol of polyacid. This final product containing prepolymer C1.12 is the composition according to the present invention.

[0259] Example 9: Acrylate functionalization with altered acidification process

[0260] The acrylated PGS (C1.1) was reacted with diethylamine (66 mg of diethylamine (DEA) / 1 g of acrylated PGS) in dichloromethane at 40 °C for 5 h, thereby providing an aminated and acrylated PGS (C1.3).

[0261] The aminated PGSA was acidified with acetic acid (6 molar equivalents compared to DEA) at room temperature for 15 min. The product was purified by brine washing and distillation.

[0262] Additives (Irgacure TPO photoinitiator and free radical initiator MEHQ) were added, and the product (C1.17) was purified by scCO2 extraction. Using 1 1H NMR spectroscopy was used to measure the proportion of groups containing a positively charged nitrogen atom (DN+) and the proportion of groups containing acrylate groups (DA). The final DN+ was 0.21 mol / mol of polyacid and the final DA was 0.30 mol / mol of polyacid. The final product containing the prepolymer C1.17 is a composition according to the present invention.

[0263] Example 10: Acrylate functionalization with further altered acidification process

[0264] The acrylated PGS (C1.1) was reacted with diethylamine (66 mg of diethylamine (DEA) / 1 g of acrylated PGS) in dichloromethane at 40 °C for 5 h, thereby providing an aminated and acrylated PGS (C1.3).

[0265] The aminated PGSA was washed with 1M HCl brine (5 min with stirring before phase separation). Then the organic layer was washed with brine twice. The organic layer was separated, dried over MgSO4 and concentrated to 50% (w / w).

[0266] Additives (Irgacure TPO photoinitiator and free radical initiator MEHQ) were added, and the product C1.18 was purified by scCO2 extraction. Using 1 1H NMR spectroscopy was used to measure the proportion of groups containing a positively charged nitrogen atom (DN+) and the proportion of groups containing acrylate groups (DA). The final DN+ was 0.21 mol / mol of polyacid and the final DA was 0.31 mol / mol of polyacid. The final product containing the prepolymer C1.18 is a composition according to the present invention.

[0267] Example 11: Acrylate functionalization with yet further altered acidification process

[0268] The acrylated PGS (C1.1) was reacted with diethylamine (46 mg of diethylamine (DEA) / 1 g of acrylated PGS) in dichloromethane at 40 °C for 23 h, thereby providing aminated and acrylated PGS (C1.3).

[0269] The aminated PGSA was acidified with formic acid (2 molar equivalents compared to DEA) for 5 min with stirring at room temperature.

[0270] An additive (Irgacure TPO photoinitiator) was added and the product C1.19 was concentrated under reduced pressure. The proportion of groups containing a positively charged nitrogen atom (DN+) and the proportion of groups containing acrylate groups (DA) were measured using 1 1H NMR spectroscopy. The final DN+ was 0.16 mol / mol polyacid and the final DA was 0.30 mol / mol polyacid. The final product containing the prepolymer C1.19 is the composition according to the invention.

[0271] Adhesive properties

[0272] The peel adhesion of the examples was tested according to the following peel method. Peel adhesion testing (at 90°) was performed on a fresh porcine epicardial tissue using an Instron. The tissue was kept in phosphate buffered saline to ensure it remained moist during testing. Unless specified, a poly(glycerol sebacate urethane) (PGSU) patch was used for testing and was approximately 200 mm thick and 6 mm in diameter. A thin layer of the prepolymer with a thickness of approximately 200 μm was applied to the patch material prior to the adhesion testing. During the curing process, a compressive force of 3 N was applied to the patch coated with the sample composition using a non-adhesive material (borosilicate glass rod, 9 mm in height), which was connected to a UV light guide (Lumen Dynamics Group Inc) with a standard tape around the glass rod and the light guide. The insertion of the borosilicate glass rod facilitated the release of the curing system from the patch without disturbing the patch / adhesive-tissue interface. The peel procedure consisted of a grip separation at a rate of 8 mm / min, thereby causing uniform patch detachment from the tissue surface. The adhesive force was recorded as the maximum force observed before adhesive failure when a sharp drop in the measured stress was observed.

[0273] The adhesion values of the cured compositions prepared from the above prepolymers are provided in Table 1 below:

[0274] Table 1

[0275]

[0276]

[0277] *The zeta potential of prepolymers C1.2 and C1.3 cannot be measured because the polymers are too hydrophobic to dissolve in the appropriate medium for measurement.

[0278] The above table shows that the adhesion values achieved using the curable compositions according to the invention (C1.4, C1.5, C1.6, C1.7, C1.8, C1.10, C2.4, C1.12, C1.17, C1.18, C1.19) are better than the adhesion values achieved using curable compositions without the invention (C1.2, C1.3, C2.1).

[0279] Zeta potential vs. adhesion comparison

[0280] The zeta potential of the prepolymers according to the invention was measured using the protocol described above. The adhesion of the prepolymer-based curable compositions was measured using the pull-off adhesion test described above. Figure 1 A graph of the zeta potential results versus the adhesion results is shown. The results show an adhesion improvement as the zeta potential of the composition increases.

[0281] Example 12: Composition formulation: Polymer cross - linking by redox (C1.13 to C1.16)

[0282] Compositions were formulated using prepolymers C1.4 and C1.12 prepared as described above. The formulations are summarized in Table 2 below:

[0283] Table 2

[0284]

[0285]

[0286] 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.

[0287] The lap shear adhesion performance test was used, such as C1.13, C1.14, C1.15 and C1.16 and prepolymer C1.4.

[0288] The protocol was adapted from ASTM F2255.1422857-1 entitled "Standard Test Method for Determining the Strength Properties of Tissue Adhesives in Lap Shear by Tensile Loading" and is as follows:

[0289] · Porcine buttocks were used as biological tissue, obtained from a local abattoir, stored in a refrigerator (2-5 °C) and tested in lap shear on the same day.

[0290] · Cut the muscle tissue with a knife and scalpel to obtain rectangular samples of the following dimensions: l = 3 cm, w = 1.5 cm, h = 0.2 - 0.4 cm. Keep the tissue samples in PBS until testing (maximum 2 h).

[0291] · For each test, remove two muscles from PBS and place them on a paper towel for 3 seconds on each side to remove excess water. The tissue is still very wet.

[0292] · Place the product to be tested at one end of the muscle sample with a spatula so that the width of the product is approximately 0.8 - 1.0 cm, as close to the boundary as possible. Then place another muscle sample on top to have an overlap of 1.5 cm × 0.8 - 1.0 cm.

[0293] · Bring the two muscle samples into contact by gently pressing the upper muscle sample against the lower muscle sample with a finger.

[0294] · For photoactivated formulations (e.g., C1.4 in the table below): Cure the product using Omnicure light (5 - second cycles, 70% intensity). Expose the overlap area to light for at least 6 cycles.

[0295] · For redox formulations: Wait until the remaining product in the microtube is completely cured.

[0296] For all samples:

[0297] · Place the assembly vertically in the fixture starting from the upper fixture. Tighten the lower fixture without pulling on the tissue.

[0298] · Set the displacement and load to zero, then raise the upper fixture at a rate of 5 mm / min until the two muscle samples separate. Record the load - displacement curve and record the maximum load before separation.

[0299] · Measure the area of the product with calipers at the end of the test. Since the product is blue and did not break into pieces during the test, it is easy to measure.

[0300] · Then divide the maximum load (in N) and the area under the curve (mJ) by the area of the polymer in the overlap region (cm 2 ). This is the apparent shear strength (N / cm 2 ) and the apparent AUC (mJ / cm 2 ).

[0301] · Take at least 4 replicates. Calculate the mean and standard deviation.

[0302] The results are shown in Table 3:

[0303] Table 3

[0304] <![CDATA[Shearing strength (N / cm 2 )]]> C1.4 1.11±0.56 C1.13 1.49±0.24 C1.14 1.62±0.38 C1.15 1.18±0.26 C1.16 1.24±0.47

Claims

1. A composition comprising a prepolymer having an activating group and an activated and functionalized group on a polymer backbone, wherein the activating group is or contains an acrylate group of the formula -C(=O)-CR p =CR q R r , where R p , R q , R r are each independently selected from H, alkyl, aryl, substituted alkyl, substituted aryl, carboxylic acid, ester, amide, amine, carbamate, ether and carbonyl; wherein the activated and functionalized group is positively charged and obtained by reacting the activating group with an amine compound; wherein the ratio of the activated and functionalized group to the number of monomer units in the main chain is 0.05 - 0.4 mol / mol monomer unit; wherein the polymer main chain of the prepolymer has the general formula (-A-B-), n , where A is derived from a substituted or unsubstituted polyol, B is derived from a substituted or unsubstituted polycarboxylic acid, and n represents an integer greater than 1; and wherein the polyol is a triol, and B is a diacid selected from the following: glutaric acid, adipic acid, pimelic acid, sebacic acid, and azelaic acid; wherein the zeta potential of the composition is in the range of 5 - 45 mV.

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

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

4. The composition according to any one of claims 1 - 3, wherein the activated and functionalized group has the following formula (III) or (IV): wherein R a , R b , R c , R d , R e and R f are independently selected from H, alkyl, alkenyl and aryl, and n1 represents an integer equal to or greater than 1.

5. The composition according to claim 4, wherein at least one of R d , R e and R f is H.

6. The composition according to any one of claims 1 - 3, wherein the polyol is glycerol or trimethylolpropane ethoxylate, and wherein B is sebacic acid.

7. The composition according to any one of claims 1 - 3, wherein the prepolymer has the following formula (VII) or (VIII): where p, q and r are integers between 1 and 20, n, m and o are integers greater than 1, and R a , R b , R c , R d , R e and R f are independently selected from H, alkyl, alkenyl and aryl.

8. The composition according to any one of claims 1 - 3, further comprising an initiator.

9. The composition according to claim 8, wherein the initiator is a redox composition comprising the following components: 0.1 - 5 wt% of a reducing agent selected from 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 - 5 wt% of an oxygen initiator selected from 4 - (diphenylphosphino)styrene and triphenylphosphine; 0.005 - 0.5 wt% of a working reagent selected from Tempol and 4 - methoxyphenol; and 0.1 - 10 wt% of an oxidizing agent selected from ammonium persulfate, potassium persulfate, and benzoyl peroxide.

10. The composition according to claim 8, wherein the initiator is a photoinitiator.

11. The composition according to claim 10, wherein the photoinitiator is selected from 2,2 - dimethoxy - 2 - phenyl - acetophenone, 2 - hydroxy - 1 - [4 - (hydroxyethoxy)phenyl] - 2 - methyl - 1 - propanone, 1 - hydroxycyclohexyl - 1 - phenyl - ketone, 2 - hydroxy - 2 - methyl - l - phenyl - 1 - propanone, 2 - benzyl - 2 - (dimethylamino) - l - [4 - (morpholino)phenyl] - 1 - butanone, methyl benzoylformate, oxy - phenyl - acetic acid - 2 - [2 - oxo - 2 - phenyl - acetoxy - ethoxy] - ethyl ester, 2 - methyl - l - [4 - (methylthio)phenyl] - 2 - (4 - morpholino) - l - propanone, diphenyl(2,4,6 - trimethylbenzoyl) - phosphine oxide, phenylbis(2,4,6 - trimethylbenzoyl)phosphine oxide, and combinations thereof.

12. A method for preparing the composition according to any one of claims 1 - 11, comprising the following steps: i) polymerizing monomers to provide a polymer backbone; ii) Activating the monomer units of the polymer backbone to provide an activated prepolymer; and iii) Functionalizing the activated prepolymer with an amine compound to provide an activated and functionalized prepolymer; wherein the monomers providing the polymer backbone include polyols and diacids.

13. The method according to claim 12, wherein the activation in step ii) is achieved by acrylation of the hydroxyl groups to produce acrylate groups; and wherein the functionalization in step iii) is achieved by reaction of the acrylate groups with an amine compound to produce amine groups, and acidification of the amine groups to produce ammonium groups.

14. The method according to claim 13, wherein the acrylation is achieved by reaction of the hydroxyl groups with acryloyl chloride or with an isocyanate acrylate compound, and the amine compound is selected from diethylamine, triethylamine, diisopropylethylamine, dibutylamine and piperidine.

15. A method of curing the composition according to any one of claims 1-11, which comprises the step of curing the composition with a stimulant selected from light, heat and chemical initiators.

16. Use of the composition according to any one of claims 1-11 in the preparation of a product for bonding or sealing tissue.

17. A cured composition obtained by curing the composition according to any one of claims 1-11.

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