BR112017026972B1 - COMPOSITION OF SEALANT, ITS METHOD OF MANUFACTURE AND USE, CURED COMPOSITION, METHOD FOR ADHERING OR SEALING FABRIC - Google Patents

Abstract

SEALANT COMPOSITION. The present invention relates to a composition with improved adhesive and sealant properties, which comprises a) a prepolymer comprising a polymeric unit of the general formula (-A-B-)n, in which A represents a substituted or unsubstituted ester, B represents a substituted or unsubstituted acid ester comprising at least two acid ester functionalities, and n represents an integer greater than 1; wherein the content of grafted anhydrides in the composition is less than 0.05 mol/mol polyacid.

Description

AREA OF INVENTION

[0001] The present invention relates to a composition, a method of manufacturing the composition, a method of curing the composition, a cured composition obtainable therefrom, uses of the composition and methods of using the composition.

BACKGROUND OF THE INVENTION

[0002] Typically, open-heart surgery relies on a suture-based closure or ligation 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, increased risk of bleeding complications or dehiscence, and therefore worse outcomes. Furthermore, cardiopulmonary bypass (CPB) is required for open-heart surgery, and this has significant adverse effects, including an inflammatory response and potential neurological complications.

[0003] Although catheter-based interventions have recently emerged for the closure of cardiac defects such as atrial and ventricular septal defects (ASDs and VSDs) in an effort to reduce the invasiveness of the procedures, the main challenges remain the fixation of devices inside the beating heart. Specifically, the fixation of devices for catheter-based closure of septal heart defects currently relies on mechanical means of tissue grasping. This can cause damage to critical structures such as heart valves or specialized conduction tissue. Furthermore, if there are inadequate tissue margins around the defects, the prosthesis may shift, damaging neighboring structures and furthermore leaving residual defects, limiting the application of the device. Therefore, the referred methods can only be applied in selected patients, depending on the anatomical location and geometric shape of the defect.

[0004] Soft tissue and compliant sealants that cure quickly, have significant sealant properties, are biocompatible and work in the presence of blood, offer a potential solution. They can be used to bond tissue surfaces or prosthetic devices to tissue together without the need for mechanical fixation or entrapment, thereby preventing tissue compression and erosion, and they can also be used for minimally invasive surgical procedures. The referred materials can find a wide range of 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 anastomosis does not always result in an instantaneous hemostatic seal, and can create irregularities in the endothelium that predispose to thrombosis. Furthermore, the presence of permanent sutures can provoke a foreign body reaction with additional inflammation and scarring at the repair site, which can increase4 the risk of late vessel occlusion. Tissue sealants can accomplish the aforementioned repairs with an instant seal and with minimal scarring or tissue damage.

[0005] An ideal tissue sealant, especially for cardiovascular and/or gastrointestinal applications, should have most of the following properties: (1) optimal viscosity or liquid-like properties prior to the curing process so as to allow easy application to a desired area while being retained at the application site, (2) minimal removal by body fluids and activation only when desired to facilitate their release and repositioning of implanted devices during minimally invasive procedures, (3) significant adhesive strength, especially in the presence of blood and/or other body fluids, (4) ability to resist mechanical loads from adhesion to highly mobile tissue, for example, heart contractions, or pulsations in great vessels, (5) ability to form a hemostatic seal and/or airtight, (6) minimal inflammatory reaction, and (7) biodegradability, which is critical to the healing process, especially important for pediatric applications since the long-term consequences of foreign materials in the growing body are uncertain .

[0006] Unfortunately, current clinically available sealants, such as medical grade cyanoacrylate (CA) or fibrin sealant, are easily washed off or cured under dynamic wet conditions, toxic and therefore cannot be used internally, and/or have poor sealing and/or adhesive properties such that they cannot withstand the forces within the heart chambers and major blood vessels. In addition, many of these sealants have activating properties that make fine adjustments or repositioning of devices very difficult. Furthermore, many sealants under development perform tissue seals only through chemical reaction with functional groups on the tissue surface, and thus become ineffective in the presence of blood.

[0007] Alternatives to cyanoacrylate have been explored. United States Patent Application No. US 8143042 B2 describes biodegradable elastomers prepared by crosslinking a prepolymer containing crosslinkable functional groups, such as acrylate groups. It also discloses that it is desirable to increase the number of free hydroxyl groups on the polymer in order to increase the viscosity of the polymer. Increasing the number of hydroxyl groups in the backbone also leads to increased solubility of hydrophobicity in physiological solutions. This suggests that the primary mechanism of polymer adhesion is chemical interactions between functional groups, for example free hydroxyl groups on the polymer and the tissue to which it is applied. However, this type of chemical interaction becomes ineffective in the presence of body fluids, especially blood, as demonstrated in Artzi et al., Adv. Mater. 21,3399-3403 (2009).

[0008] Similarly, Mahdavi, et al., 2008, PNAS, 23072312, describes nanopatterned elastomeric polymer and proposes the application of a thin layer of oxidized dextran with aldehyde functionalities (DXTA) to increase the adhesion strength of the adhesive promoting covalent crosslinking between terminal aldehyde group in DXTA with amine groups in tissue proteins.

[0009] This adhesion mechanism relies essentially on covalent bonding between radicals generated during the healing process and tissue functional groups has several limitations. The use of adhesives with reactive chemistry requires tissue surfaces to be dry prior to application of the prepolymer, which makes it very challenging to use in cardiac applications, such as during emergency procedures. Additionally, reactive chemistry can denature proteins or tissue and stimulate undesirable immune reactions such as local inflammation which can lead to adhesive rejection. Furthermore, reactive chemistry that only bonds to the fabric surface will likely have less adhesion since the interface will be more distinct, and therefore there will be a mismatch in mechanical properties at the interface between the glue and the fabric.

[0010] Elastomeric crosslinked polyesters are disclosed in United States Patent Application No. US 20130231412 A1. Biodegradable polymers are disclosed in US Patent Application No. US 7722894 B2. Adhesive articles are disclosed in International Patent Application No. WO/2009/067482 A1 and International Patent Application No. WO/2014/190302 A1. Blood-resistant surgical glue is described 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, Nora Lang, Maria Pereira et al. and in International Patent Application No. WO/2014/190302 Al. However, a need still exists for an improved, commercially viable tissue sealant/adhesive that can be readily applied to the desired site, remain in place at the desired site before of the healing process and is not washed away by body fluids, is biocompatible (non-toxic), and exhibits strong sealing/adhesive forces such as those found within heart chambers and major blood vessels even in the presence of body fluids such as blood.

SUMMARY OF THE INVENTION

[0011] The present invention provides a composition comprising: a prepolymer comprising a polymer unit of the general formula (-A-B-)n, wherein A represents a substituted or unsubstituted ester, B represents a substituted or unsubstituted acid ester comprising at least two acid ester functionalities, and n represents an integer greater than 1; wherein the content of grafted anhydrides in the composition is less than 0.05 mol/mol polyacid.

[0012] The present invention also provides a method for manufacturing the composition according to the present invention.

[0013] The present invention additionally provides a method of curing the composition according to the present invention, comprising curing the composition with a stimulus, for example light in the presence of a photoinitiator.

[0014] The present invention also provides a cured composition obtainable by the curing method according to the present invention. According to a preferred embodiment, said cured composition is a sealant, i.e. it can provide a seal, preventing leakage of fluids or gas.

[0015] The present invention additionally provides methods of using and utilizing the composition according to the present invention for gluing or sealing tissue or for adhering tissue to the surface of a medical device.

[0016] The present invention also provides a method for sealing fabric, the method comprising applying the composition according to the present invention to the surface of the fabric and curing the composition.

[0017] The present invention additionally provides a method for adhering tissue to the surface of a medical device, the method comprises applying the composition according to the present invention to the surface of the tissue and/or medical device and curing the composition. In preferred embodiments, a medical device can be adhered to another medical device, or parts of medical devices can be adhered together in a medical device assembly.

BRIEF DESCRIPTION OF THE FIGURES

[0018] Figures 1 to 3 and 5 are graphs showing the explosion performance of compositions according to the present invention.

[0019] Figure 4 is a photograph of a femoral artery graft sealed using a composition according to the present invention.

[0020] Figure 6 depicts bone growth in a defect of calvarial bones in the presence of fibrin only (FN), fibrin coated with polytetrafluoroethylene (PTFE), or fibrin coated with polyglycerol sebacate acrylate (PGSA). It shows a 3D representation of a mouse head, 3D tomodensitometric reconstruction of calvarial defect at week 0 and week 4, and the volume of new bone formation in calvarial defect with different membranes.

[0021] Figure 7 is a graph showing the release of a model drug from PGSA disks with different thicknesses.

[0022] Figure 8 is a graph showing the release of a model drug from PGSA discs with different degrees of acrylation.

[0023] Figure 9 is a 3D printing photograph of PGSA.

DETAILED DESCRIPTION OF THE INVENTION Prepolymer

[0024] The prepolymer according to the present invention comprises a polymeric unit of the general formula (-A-B-)n, in which A represents a substituted or unsubstituted ester, B represents a substituted or unsubstituted acid or acid ester comprising at least two acid or acid ester functionalities; and n represents an integer greater than 1.

[0025] Component A may be derived from a polyol, such as a diol, triol, tetraol or higher. Suitable polyols include diols, such as alkane diols; triols, such as glycerol, trimethylalpropane, triethanolamine; tetraols such as erythritol, pentaerythritol; and higher polyols, such as sorbitol. Unsaturated diols, such as tetradeca-2,12-diene-1,14-diol, or other diols including macromonomer diols such as, for example, polyethylene oxide, and N-methyldiethaneamine (MDEA) can also be used. Preferably, the polyol is substituted or unsubstituted glycerol.

[0026] Component B may be derived from a polyacid, such as a diacid or higher order acid. A wide variety of diacids or higher order acids can be used. Examples of acids include, but are not limited to, glutaric acid (5 carbons), adipic acid (6 carbons), pimelic acid (7 carbons), sebacic acid (8 carbons), and azelaic acid (nine carbons). Examples of long chain diacids include diacids having more than 10, more than 15, more than 20, and more than 25 carbon atoms. Non-aliphatic diacids can also be used. For example, versions of the above diacids having one or more double bonds can be used to produce polyol-diacid copolymers. Preferably the diacid is substituted or unsubstituted sebacic acid.

[0027] Polyol-based polymers described in United States Patent Application Publication No. 2011-0008277, United States Patent No. 7,722,894 and United States Patent No. 8,143,042, the contents of which are hereby incorporated by way of reference, they can also be used as a prepolymer to form elastomeric polymeric materials.

[0028] Various substituents, such as amines, aldehydes, hydrazides, acrylates and aromatic groups, can be incorporated within the carbon chain. Examples of aromatic diacids include terephthalic acid and carboxyphenoxypropane. The diacids furthermore can also include substituents. For example, reactive groups such as amine and hydroxyl 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.

[0029] The prepolymer may additionally comprise a polyamide or polyurethane backbone. For example, b polyamine (comprising two or more amino groups) can be used to react with polyacid together with polyol or after reacting with polyol. Exemplary poly(amide ester) include those described in Cheng, et al., Adv. Mater. 2011, 23, 1195-11100, the contents of which are hereby incorporated into this patent application by reference. In other examples, polyisocyanates (comprising two or more isocyanate groups) can be used to react with polyacid along with polyol or after reacting with polyol. Examples of polyester urethanes include those described in US Patent No. US/2013/231412.

[0030] The weight average molecular weight of the prepolymer, as measured by Gel Permeation Chromatography equipped with a refractive index, can be from about 1,000 Daltons to about 1,000,000 Daltons, from 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, 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. Daltons. The weight average molecular weight can be from about 1000 Daltons to about 10,000 Daltons, from about 2000 Daltons to about 10,000 Daltons, from about 3000 Daltons to about 10,000 Daltons from about 5,000 Daltons to about 10,000 Daltons. Preferably, it is about 3000 Daltons.

[0031] The term "about" as used herein in this patent application means within 10%, preferably within 8%, and most preferably within 5% of a given value or range. According to a specific embodiment, "about X" means X.

[0032] The prepolymer may have a polydispersity, as measured by Gel Permeation Chromatography equipped with a refractive index, below 20.0, more preferably below 10.0, most preferably below 5 .0, and even more preferably below 2.5. Preferably, it is about 2.5.

[0033] The prepolymer may have a melt viscosity at 80°C of between 100 and 2000 cP, more preferably between 200 and 1000 cP, and even more preferably between 300 and 500 cP.

[0034] The prepolymer may have an acid number between 1 and 200 mg KOH/g polymer, more preferably between 10 and 100 mg KOH/g polymer, and even more preferably between 50 and 100 mg of KOH/g of polymer. Preferably, it is about 80 mg KOH/g polymer

[0035] The molar ratios of the polyol to the polyacid in the prepolymer can be 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 and 1:10. 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1. Molar ratios of polyol to polyacid can also be 2:3, 3:2, 3:4, or 4:3. The polymer can also be the result of a mixture of two or more different proportions. Preferably, it is about 1:1.

Activated Prepolymer

[0036] The prepolymer of the present invention is preferably activated. It can be activated by introducing functional groups that can react or be reacted to form crosslinks. The prepolymer is activated by reacting one or more functional groups on the prepolymer backbone with one or more functional groups that can react or be reacted to form crosslinks resulting in a cured polymer.

[0037] Suitable functional groups to be activated on the backbone of the prepolymer include hydroxy groups, carboxylic acid groups, amines, and combinations thereof, preferably hydroxy and/or carboxylic acid. The free hydroxyl or carboxylic acid groups on the prepolymer can be activated by functionalizing the hydroxyl groups with a moiety which can form a crosslink between polymer chains. The groups that are activated can be free hydroxyl or carboxylic acid groups on Moieties A and/or B in the prepolymer.

[0038] The free hydroxy or carboxylic acid groups can be functionalized with a variety of functional groups, for example, vinyl groups. Vinyl groups can be introduced by a variety of techniques known in the art, such as by vinylation or acrylation. According to the present invention, vinyl groups contain the following structure - CR1=CR2R3 where R1, R2, R3 are selected independently of each other from the group consisting of H, alkyl such as methyl, ethyl, aryl such as phenyl, substituted alkyl, substituted aryl, carboxylic acid, ester, amide, amine, urethane, ether and carbonyl.

[0039] Preferably, the functional group is or contains an acrylate group. According to the present invention, acrylate groups are moieties containing substituted or unsubstituted acryloyl group. The acrylate may contain the following group: -C(=O)-CR1=CR2R3, wherein R1, R2, R3 are selected independently of one another 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.

[0040] Preferably, R1, R2 and R3 are H; or R1 is CH3, R2 and R3 are H; or R1 and R2 are H and R3 is CH3; or R1 and R2 are H and R3 is phenyl.

[0041] Vinyl groups can also be incorporated into the backbone of the prepolymer by using free carboxyl groups on the prepolymer. For example, hydroxyethyl methacrylate can be incorporated across the COOH groups of the prepolymer using carbonyl diimidazole activation chemistry.

[0042] The degree of activation can vary and can be from 0.2 to 0.9 mol/mol of polyacid or polyol, preferably from 0.3 to 0.8 mol/mol of polyacid or polyol and so the more preferably from 0.4 to 0.6 mol/mol polyacid or polyol, such as 0.5 mol/mol polyacid or polyol to obtain optimum burst performance properties at room temperature or at elevated temperature up to 40°C, preferably at 37°C. It is more preferred when the degree of activation is as described above and the reactive functional group is acrylate, i.e. degree of acrylation as above.

[0043] The preferably activated prepolymer has the general formula (I): where n and p each independently represent an integer equal to or greater than 1, and where R2 in each individual unit represents hydrogen or a polymer chain, or -C(=O)- CR3=CR4R5, where R3, R4 , R-5 are selected independently of one another 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.

[0044] 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.

[0045] Preferably, p is an integer from 1 to 20, more preferably from 2 to 10, even more preferably from 4 to 10. It is most preferred when p=8.

[0046] The preferred prepolymer has the following structure: where n represents an integer equal to or greater than 1

[0047] In addition to acrylates or other vinyl groups, other agents can be used to activate the prepolymer. Examples of similar agents include, but are not limited to, glycidyl, epichlorohydrin, triphenylphosphine, diethyl azodicarboxylate (DEAD), diazirin, divinyladipate, and divinylsebacate with the use of enzymes as catalysts, phosgene-type reagents, chlorides of diacids, bis-anhydrides, bis-halides, metallic surfaces, and combinations thereof. The agents can additionally include functional groups of isocyanate, aldehyde, epoxy, vinyl ether, thiol, DOPA residues or N-Hydroxysuccinimide.

[0048] The activated prepolymer can be further reacted with one or more additional materials to modify the crosslinks between the polymer chains. For example, before or during the curing/crosslinking procedure, one or more hydrogel or other oligomeric or monomeric or polymeric precursors (e.g., precursors that may 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, trimethylpropane trimethacrylate, pentaerythritol trimethacrylate, pentaerythritol tetramethacrylate, ethylene glycol dimethacrylate. dipentaerythritol pentaacrylate, Bis-GMA (Bis phenol A glycidal methacrylate) and TEGDMA (triethylene glycol dimethacrylate), sucrose acrylate; other thiol-based precursors (monomeric or polymeric); other epoxy-based precursors; and combinations thereof, can be reacted with the acrylated prepolymer (eg, PGSA).

[0049] The activated prepolymer can be manufactured in the presence of and/or mixed with a coloring agent. Preferred examples of coloring agents are those recommended by the US Food and Drug Administration FDA for use in medical devices, pharmaceuticals or cosmetics. See https://www.fda.gov/ForIndustry/ColorAdditives/ColorAdditiveInventories/. Most preferably, this agent is FD&C 1.

anhydrides

[0050] The inventors of the present invention realized that anhydride compounds can be generated from the activation of the prepolymer, for example through the reaction of acryloyl chloride (AcCl) and free carboxylic acids. An example of a similar anhydride has the general formula (II): wherein p and each individually represent an integer equal to or greater than 1; wherein R6 and R6' in each individual unit are independent and can be a polymer chain or R6 and R6' in each individual unit are independent and can be -C(=O)-CR3=CR4R5, where R3, R4, R5 are selected independently of one another 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; or R6 and R6' on each individual unit are independent and may be alkyl, aryl, heterocycles, cycloalkyl, aromatic heterocycles, multicycloalkyl, ester, ether, halide, carboxylic acid, amino, alkylamino, dialkylamino, trialkylamino, groups starch, carbamoyl, thioether, thiol, alkoxy, or ureido.

[0051] p can be an integer from 1 to 20, from 2 to 10, or even from 4 to 10, such as when p=8.

[0052] The anhydride can have the following structure: wherein R6 or R6' independently represent a polymer chain or

[0053] During prepolymer activation, both asymmetric and symmetric anhydrides can be generated.

[0054] An asymmetric anhydride (also referred to as mixed anhydride) is a carboxylic acid anhydride that has the following general structural formula: wherein R1 and R2 are different, and R1 and R2 are selected from the group of hydrogen atoms, alkyl groups, aryl groups.

[0055] A symmetrical anhydride is a carboxylic acid anhydride that has the following general structural formula: where R1 is selected from the group of hydrogen atoms, alkyl groups, aryl groups.

[0056] The inventors of the present invention have now shown that this presence of anhydrides is correlated with instability of the prepolymer, leading to an increase in the level of impurities (e.g. low molecular weight acrylates) over time and the composition being very difficult to apply. It was therefore necessary to obtain a stable composition comprising the prepolymer which can be used as a sealant and/or adhesive with limited change in impurity level over time, limited molecular weight evolution, and therefore limited change in viscosity.

[0057] According to the present invention the molar ratio of the total anhydride content grafted in the composition is less than 0.05 mol/mol polyacid as measured by nuclear magnetic resonance (NMR). Preferably there is no graft anhydride present in the composition. More preferably there is no anhydride, grafted or ungrafted, present in the composition.

[0058] The content of grafted anhydrides in the composition can be controlled during synthesis by ethanol capping or using any miscellaneous nucleophilic substitution reaction. These chemical reactions are common knowledge in the art. Suitable reagents for this reaction include alcohols, amines or sulfhydryl compounds. The addition of ethanol is preferably at a temperature in the range of 30 to 50°C, preferably 35 to 45°C, for example at 40°C. The duration of the ethanol capping step is preferably conducted for 10 and 40 hours, more preferably for 24 hours. The volume ratio of polymer solution (~10% wt/vol) to ethanol is in the range of 20:1, more preferably in the range of 10:1, and even more preferably in the range of 5 :1.

[0059] After the capping steps, the structure of the ends of the free carboxylic acids in the pre-chains of activated polymers becomes: wherein p and each individually represent an integer equal to or greater than 1; wherein R6 and R6' in each individual unit are independent and can be a polymer chain or R6 and R6' in each individual unit are independent and can be -C(=O)-CR3=CR4R5, where R3, R4, R5 are selected independently of one another 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; or R6 and R6' on each individual unit are independent and can be -H, alkyl, aryl, heterocycles, cycloalkyl, aromatic heterocycles, multicycloalkyl, ester, ether, halide, carboxylic acid, amino, alkylamino, dialkylamino groups , trialkylamino, starch, carbamoyl, thioether, thiol, alkoxy, or ureido; wherein R7 is selected from the group consisting of -H, alkyl such as methyl or ethyl, aryl such as phenyl, substituted alkyl, substituted aryl, amine, urethane, thiol or thioester.

[0060] In the case of capping with ethanol R7 is -CH2CH3

[0061] Unreacted nucleophilic groups can be partially or fully blocked or protected after activation of the prepolymer. Examples of blocking or protective reactions are common knowledge in the art. Protective or blocking groups include acyl; alkyl, cyclic or acyclic, branched or unbranched, substituted or unsubstituted; alkenyl, cyclic or acyclic, branched or unbranched, substituted or unsubstituted; cyclic or acyclic, branched or unbranched, substituted or unsubstituted alkynyl; cyclic or acyclic heteroalkyl, branched or unbranched, substituted or unsubstituted; cyclic or acyclic heteroalkenyl, branched or unbranched, substituted or unsubstituted; or cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroalkynyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl.

Cure

[0062] The composition according to the present invention can be a surgical composition and can be used as tissue sealants and/or adhesives. The composition has flow characteristics such that it can be applied to the desired area via a syringe or a catheter yet is sufficiently viscous to remain in place at the site of application without being washed away by bodily fluids such as water and/or blood.

[0063] Preferably, the viscosity of the composition is 500 cP to 100000 cP, more preferably 1000 to 50000 cP, even more preferably 2000 to 40000 cP, and most preferably 2500 to 25000 cP . Viscosity analysis is performed using a Brookfield DV-II + Pro viscometer with a 2.2 mL chamber and SC4-14 spindle, the speed during analysis is varied from 5 to 80 rpm. The above-mentioned viscosity is present in the relevant temperature range for medical application, i.e. room temperature up to 40°C, preferably 37°C.

[0064] The composition is also sufficiently hydrophobic to resist removal by bodily fluids such as blood. This facilitates release to the desired site as well as repositioning of implanted devices using the composition of the invention during minimally invasive surgery. Hydrophobicity is dependent on the chemical composition of the prepolymer, including the hydrophobic nature of the polymer backbone (eg longer alkyl chains are more hydrophobic than shorter alkyl chains) and the degree of activation. The prepolymer of the present invention may already contain crosslinks prior to curing, but typically is not fully crosslinked since it is soluble in organic solvents such as dichloromethane or ethyl acetate. The composition of the invention can be incubated in body fluids, such as blood, prior to administration and the curing process, without a substantial reduction in seal strength when cured.

[0065] The composition of the invention is stable in body fluids such as blood. More particularly, the composition of the invention does not spontaneously crosslink in body fluids absent the presence of an intentionally applied stimulus such as light, for example UV light, heat, or chemical initiator to initiate crosslinking.

[0066] The composition can be cured using a reaction initiated by free radicals, such as, for example, by photoinitiated polymerization, by thermally initiated polymerization, and by redox reaction initiated polymerization.

[0067] Preferably, the composition is irradiated with light, for example 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-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), methylbenzoylformate (Darocur MBF), oxyphenylacetic 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), phosphine oxide, phenyl bis(2,4,6-trimethyl benzoyl) (Irgacure 819), and combinations thereof.

[0068] Preferably, the composition is irradiated with visible light (typically blue light 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.

[0069] In composition applications involving in vivo photopolymerization and other medical applications, the use of cytocompatible photoinitiators is preferred and may be required by regulatory agencies. The Irgacure 2959 photoinitiator can be used which causes minimal cytotoxicity (cell death) over a wide range of species and mammalian cell types, however it is possible to reduce this risk by using non-toxic amounts.

[0070] In order for photopolymerization to occur, the composition (and the substrate to which it is applied, if applicable) preferably is sufficiently transparent to light, even if it is colored.

[0071] In applications where the composition is cured in vivo, the temperature at which the curing process takes place is preferably controlled so as not to damage the tissue to which the composition has been applied. This control can be handled by reducing the time of exposure to curing light (eg less than 60 seconds, preferably less than 30 seconds). Preferably, the composition is not heated above 45°C during irradiation, more preferably not above 37°C, and even more preferably not above 25°C.

[0072] In addition to photochemical crosslinking, the composition can be thermally cured, by Mitsunobu-type reaction, by redox-initiated polymerization, for example, benzoyl peroxide, N,N,-dimethyl-p-toluidine, ammonium persulfate , or tetramethylenediamine (TEMED), and by a Michael-type addition reaction using a difunctional sulfhydryl compound.

[0073] After polymerization, the prepolymer forms a crosslinked network with improved sealing properties and exhibits significant sealing strength even in the presence of blood and other body fluids. The sealant of the Invention obtained after the curing procedure is preferably elastic enough to resist movement of the underlying tissue, for example, contractions of the heart and blood vessels. The sealant can provide a seal, preventing leakage of fluids or gas. The sealant is preferably biodegradable and biocompatible, causing minimal inflammatory reaction. Preferably the sealant is elastomeric.

[0074] Biodegradability can be assessed in vitro, such as in phosphate buffered saline (PBS) or under acidic or alkaline conditions. Biodegradability can also be evaluated in vivo, such as in an animal, for example mice, rats, dogs, pigs or humans. The rate of degradation can be evaluated by measuring the loss of weight and/or thickness of the polymer over time in vitro or in vivo.

[0075] The cured composition can have a burst pressure of more than 80 mmHg, preferably in a range of 100 mmHg to 200 mmHg or greater, for example 400 mmHg or 500 mmHg. Burst force or pressure refers to the pressure value obtained to burst an explanted porcine carotid arterial vessel which has an incision coated with the composition.

[0076] The cured, isolated or coated composition on a plaster or fabric preferably also has an adhesive pull-out force at 90° of at least 0.3 N/cm 2 , more preferably at least 0.5 N /cm2 and even more preferably at least 2 N/cm2, for example 1.5 N/cm2 to 2 N/cm2, or greater. Extraction adhesive strength refers to the adhesion value obtained by affixing an adhesive specimen or article to wet tissue, such as the epicardial surface of cardiac tissue, blood vessels, or the serosal side of porcine intestinal tissue, immobilized on a smooth substrate, such as like a metallic tip. The 90° pull-off adhesion test determines the greatest perpendicular force (in tension) that a surface area can withstand before the adhesive peels.

[0077] According to a preferred embodiment, the composition of the invention is cured in light and in the presence of a photoinitiator and the cured composition has an adhesive extraction force at 90° of at least 0.5 N/cm2, so preferably at least 1 N/cm2 and even more preferably at least 2 N/cm2, for example 1.5 N/cm2 to 2 N/cm2, but preferably more than 5 N/cm2, for example up to 6 N/cm2 or 7 N/cm2 or greater.

[0078] The composition of the present invention when cured in light and in the presence of a photoinitiator preferably has one or more of the following properties: i) extraction strength at 90° of more than 0.3 N/cm 2 , so 0.5 N/cm 2 or greater is preferred; and ii) burst performance of more than 80 mmHg, preferably 100 to 200 mmHg or greater.

[0079] The composition of the present invention is used as a sealant, that is, it is capable, after curing, of preventing leakage (eg fluid, gas) by forming a barrier or by filling an empty volume.

[0080] According to a preferred embodiment, the composition of the invention is also used as an adhesive, that is to say, it is capable, after curing, of binding strongly to a surface or of bonding one surface to another.

[0081] In addition to adhesion and wet biological tissue sealing, the composition can adhere to and seal a variety of hydrophilic or hydrophobic substrates, natural or synthetic, including polyethylene terephthalate, expanded polyethylene terephthalate, polyester, polypropylene, silicones, polyurethanes, acrylics, fixed tissue (eg, pericardium), ceramics, or any combination thereof.

Manufacturing Method

[0082] The method for manufacturing the composition of the present invention comprises: i) polycondensation of a first component comprising two or more functionalities of the general formula —OR, where R of each group is independently hydrogen or alkyl; and a second component comprising two or more acid ester functionalities; ii) activating the prepolymer produced by step i); iii) control of the anhydride content; optionally iv) blocking free hydroxyl groups; and/or optionally v) purifying the activated prepolymer produced by steps ii) and/or iii) and/or iv).

[0083] Said first component may be a polyol, such as a diol, triol, tetraol or higher. Suitable polyols include diols, such as alkane diols; triols, such as glycerol, trimethylalpropane, triethanolamine; tetraols such as erythritol, pentaerythritol; and higher polyols, such as sorbitol. Unsaturated diols, such as tetradeca-2,12-diene-1,14-diol, or other diols including macromonomer diols such as polyethylene oxide, and N-methyldiethaneamine (MDEA) can also be used. Preferably, the polyol is substituted or unsubstituted glycerol.

[0084] Said second component may be a polyacid, such as a diacid or higher order acid. A wide variety of diacids or higher order acids can be used. Examples of acids include, but are not limited to, glutaric acid (5 carbons), adipic acid (6 carbons), pimelic acid (7 carbons), sebacic acid (8 carbons), and azelaic acid (nine carbons). Examples of long chain diacids include diacids having more than 10, more than 15, more than 20, and more than 25 carbon atoms. Non-aliphatic diacids can also be used. For example, versions of the above diacids having one or more double bonds can be used to produce polyol-diacid copolymers.

[0085] Examples of aromatic diacids include terephthalic acid and carboxyphenoxypropane. The diacids can furthermore also include substituents, for example amine and hydroxyl substituents.

[0086] Preferably the diacid is substituted or unsubstituted sebacic acid.

[0087] The aforementioned first and second components are added together in a range of molar ratio of the first component : the second component from 0.5:1 to 1.5:1, preferably from 0.9:1.1 and most preferred 1:1. Where the first component is glycerol and the second component 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 extra hydroxyl group on glycerol is used during the activation step.

[0088] The conditions for step i) are not especially limited but may include a temperature range of 100 to 140°C, preferably 120 to 130°C, an inert atmosphere, preferably comprising nitrogen, and under vacuum.

[0089] The activating agent of step ii) is preferably an acrylating agent which comprises an acrylate group which are substituted or unsubstituted acryloyl group-containing moieties. The acrylate may contain the following group: -C(=O)- CR1=CR2R3, where R1, R2, R3 are selected independently of one another 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.

[0090] Preferably, R1, R2 and R3 are H; or R1 is CH3, R2 and R3 are H; or R1 and R2 are H and R3 is CH3; or R1 and R2 are H and R3 is phenyl.

[0091] Most preferably, the acrylating agent is acryloyl chloride.

[0092] During the acrylation process, anhydrides can be formed resulting from the reaction of the acrylated monomer with any carboxylic acid groups. According to a preferred embodiment, the anhydride content is controlled in step (iii) by ethanol capping or using any other nucleophilic substitution reaction. Suitable reagents for this step (iii) include alcohols, amines or sulfhydryl compounds. The addition of ethanol is preferably at a temperature in the range of 30 to 50°C, preferably 35 to 45°C, for example at 40°C. The duration of the ethanol capping step is preferably conducted for 10 and 40 hours, more preferably for 24 hours. The volumetric ratio of polymer solution to ethanol is in the range of 20:1, more preferably in the range of 10:1 and even more preferably in the range of 5:1.

[0093] Blocking or protection of hydroxyls can be performed (step iv)). Techniques known in the art can be applied. Preferably, the hydroxyls are blocked through an acylation reaction using a compound such as ethanoyl chloride.

[0094] Residual levels of grafted anhydrides may also be present, preferably at a level below 0.05 mol/mol polyacid.

[0095] The formation of grafted anhydrides can also be prevented by blocking any free carboxylic acid groups prior to activation, ie, step (iv) occurring before step (ii).

[0096] Steps i) to iv) may be performed in the presence of one or more solvents or catalysts, examples including dichloromethane (DCM), ethyl acetate (EtOAc) dimethylaminopyridine (DMAP), and triethylamine (TEA) or any combination thereof.

[0097] Purification step v) is carried out to ensure that any unreacted solvents and products are removed from the prepolymer produced by step iii) and iv). This step may include a filtration step and/or a water wash step. When this step v) comprises a step of washing with water, conditions must be favored to allow a rapid phase separation between the organic and aqueous phases. For example, phase separation during water washes can be improved by using salts solubilized in the aqueous phase. Examples of salts include, but are not limited to, sodium chloride, sodium bicarbonate. Alternatively, salts produced during the reaction can be removed by filtration using an organic solvent such as ethyl acetate, n-methyl tetrahydrofuran, tetrahydrofuran.

[0098] Preferably the purification step may also be followed by one or more steps, more preferably by all the steps that follow, including addition of free radical inhibitor, for example butylated hydroxytoluene (BHT), monomethylether - hydroquinone (MEHQ), phenylbutyl nitrone (PBN), and/or photoinitiator, e.g. Irgacure 2595 or diphenyl trimethyl phosphine oxide (TPO), evaporation and/or solvent extraction, preferably via supercritical CO2 to ensure efficient removal of solvents and impurities without interfering with prepolymer activation.

Usage Methods

[0099] The composition can be applied directly to the desired site, such as by application with a syringe or a catheter, through a spreading tip, by spraying or using a brush. Preferably the composition is sufficiently non-viscous to be injectable through a syringe needle having a gauge of 14 to 20, preferably 14 to 18, yet is sufficiently viscous to remain in place at the site of administration with minimal washout. . The composition can be mixed prior to application or during application with a photoinitiator, a stabilizer, a therapeutic, a prophylactic, and/or a diagnostic agent, and/or one or more excipients.

[00100] The materials can be used directly, that is, applied directly to the site to be sealed or adhered. Alternatively, the materials can be applied to a device, such as a patch or tape, to adhere the patch to the desired location. Conventional plaster, plaster materials or graft materials, natural or synthetic, known in the art may be used. Plasters for use with major blood vessels, cardiac tissue, and/or hard to treat wounds (e.g., diabetic ulcers) are known in the art. Biocompatible and biodegradable surgical tape can be used, for example, to stop bleeding during surgery. As the tape is biodegradable, it does not need to be removed before the surgeon sutures the wound closed. Examples of other suitable materials include polyethylene terephthalate, expanded polyethylene terephthalate, polyester, polypropylene, silicones, polyurethanes, acrylics, fixed tissue (e.g., pericardium), ceramics, or any combinations thereof.

[00101] The thickness of the composition or adhesive layer can be varied depending on the application and the site of administration. The thickness of the coatings can be at least about 50 microns, 60 microns, 70 microns, 74 microns, 75 microns, 80 microns, 100 microns, 125 microns, 150 microns, 175 microns, 200 microns, 225 microns, 250 microns , 275 micron, 300 micron, 325 micron, 350 micron, 375 micron, 400 micron, 425 micron, 450 micron, 475 micron, 500 micron, 525 micron, 550 micron, 575 micron, 600 micron, 625 micron, 650 micron, 675 micron, 700 micron, or 725 micron.

[00102] The sealing and adhesive properties of the activated prepolymer can be induced through different approaches. The preferred approach is through a light stimulus in the presence of a photoinitiator. Other potential stimuli include heat in the presence of suitable initiators known in the art, or the use of reactive chemicals that can induce network polymerization as disclosed above.

[00103] The sealant/adhesive strength can be improved by subjecting the composition to preload during the curing procedure. This can be particularly useful for embodiments involving a plaster in which the prepolymer is coated onto a plaster and then applied to a fabric. The preload applied to the coated plaster during the curing procedure can be varied as long as it results in an increase in adhesive strength. The preload force applied to the plaster can be from about 0.5 N to about 10 N, preferably from about 1 N to about 8 N, more preferably from about about 2 N to about 8 N, most preferably from about 3 N to about 7 N. Preloading can help the adhesive penetrate into the tissue.

Uses A. Tissue sealing and adhesion

[00104] The composition according to the invention can be used to adhere or seal targeted surfaces including tissue, graft material such as PTFE-based graft, or any combination thereof. The method of adhering or sealing target surfaces comprises applying the composition to the surface and curing the composition.

[00105] According to a special embodiment, the composition of the Invention is used to form a barrier or to fill a void, especially in order to prevent leakage, for example, of fluid, gas, etc. For example, the composition of the Invention can be used as a surgical sealant. Examples of applications include stopping bleeding, for example, due to injury or trauma or during surgery such as after suturing a graft to a vessel or after vascular access in endovascular procedures. Examples of applications include use as a suturing aid in vascular anastomosis, and as a suturing aid in ePTFE grafts, for example, ePTFE vascular grafts. The sealant does not need to be removed before or after the surgeon sutures the wound closed as it will degrade over time. According to other applications, the composition of the Invention can additionally be used in sutureless conditions, for example, for sutureless closure of vascular incisions. Other types of wounds that may be treated include, but are not limited to, wounds that leak, wounds that are difficult to close, or that fail to heal properly through normal physiological mechanisms. The application can be carried out both inside and outside the body, for human or veterinary use.

[00106] Unlike conventional fabric adhesives that activate spontaneously during application or in the presence of water, or adhesives that are hydrophilic and therefore subject to washing before the curing process, the composition according to the invention can be applied to wet substrates without activation or displacement. The composition can also be applied to dry substrates.

[00107] The composition can also be used to adhere fabric to the surface of a medical device. The composition can be used in medical devices, either as part or all of a device or for adhering a device to tissue. The method of adhering tissue to the surface of a medical device comprises applying the composition to the surface of the tissue and/or medical device and curing the composition. The composition can also be used to bond tissue, including one or more tissues in vivo.

[00108] The composition according to the invention can also be manufactured inside a biodegradable stent. The stent can increase the diameter of a blood vessel to increase flow through the vessel, but because the stent is biodegradable, the blood vessel can increase in diameter with a reduced risk of thrombosis or by covering the stent with scar tissue, which can narrow the blood vessel. The composition can coat an outer surface of a stent to help adhere the stent to a vessel wall in a manner that is less tissue damaging than an uncovered stent or to prevent displacement within the body. Similarly, the composition can cover the surface of any devices which are in contact with tissue in order to provide a suitable interface which can be adhesive to the tissue.

[00109] The composition according to the present invention can be used in a variety of other applications where an adhesive or a sealant is required. These include, but are not limited to, air leaks after lung resection; to reduce the time for surgical procedures; to seal the dura mater; to facilitate laparoscopic procedures; as a degradable skin adhesive; as a hernia matrix to prevent or reduce the need for staples or tacks; to prevent blood loss; to manipulate organs or tissues during surgical procedures; to fix corneal transplants in place; to arrange a heart to release drugs and/or to reduce the dilation of the heart after myocardial infarction; for attaching other material to a fabric; to augment sutures or staples; to distribute forces through tissue; to prevent leaks; as a barrier membrane over the skin to prevent water evaporation from burned skin; as a plaster for delivering anti-scarring or antimicrobial medication; for devices affixed to tissue; for securing devices to the mucous membrane such as tape for securing devices within an oral cavity, such as for holding dentures and oral appliances; as a tape to anchor soft tissue to bone; as a moldable barrier in guided bone repair and, preventing the formation of holes in the tissue, reinforcing / increasing the mechanical properties of tissues, etc.

B. Release of bioactive molecules

[00110] The composition according to the described invention may also contain one or more pharmaceutical, therapeutic, prophylactic, and/or diagnostic agents that are released during the period of time that the material functions as a sealant/adhesive. The agent may be a small molecule agent, for example having a molecular weight of less than 2000, 1500, 1000, 750, or 500 Da, a biomolecule, for example peptide, protein, enzyme, nucleic acid, polysaccharide, growth factors, cell adhesion sequences such as RGD or integrin sequences, extracellular matrix components, or combinations thereof. Examples of classes of small molecule agents include, but are not limited to, anti-inflammatories, analgesics, antimicrobial agents, and combinations thereof. Examples of growth factors include, without limitation, TGF-β, acidiferous fibroblast growth factor, basic fibroblast growth factor, epidermal growth factor, IGF-I and II, vascular endothelium-derived growth factor, mor- bone phogenetics, platelet-derived growth factor, heparin-binding growth factor, hematopoietic growth factor, peptide growth factor, or nucleic acids. Examples of 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 composition of the present invention.

[00111] Functional groups on the prepolymer that have not been activated can be used to covalently attach one or more agents, such as small molecule agents and/or biomolecules. Alternatively, the one or more agents can be physically entrapped within the cured composition by curing the composition in the presence of the agent.

[00112] According to preferred embodiments, slower release profiles of bioactive molecules will be obtained by increasing the degree of acrylation according to the Invention.

C. tissue support

[00113] The materials can be used to create tissue supports forming articles modeled within the body to serve a mechanical function. Patterned articles can be produced by a variety of manufacturing techniques known in the art, including 3D printing.

[00114] The articles referred to can perform functions such as holding two tissues together or positioning the tissue in a specific position inside or outside the body.

[00115] The tissue can be coated with a layer of the materials, for example the lumen of a tissue such as a blood vessel to prevent restenosis, re-closure or vasospasm after vascular intervention.

[00116] The composition may 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 seeded with one or more of tenocytes, fibroblasts, ligament cells, endothelial cells, lung cells, epithelial cells, smooth muscle cells, cardiac muscle cells, skeletal muscle cells, islet cells, nerve cells, hepatocytes , kidney cells, bladder cells, urothelial cells, chondrocytes, and bone-forming cells. The combination of cells with the material can be used to support tissue repair and regeneration.

D. Anti-adhesion barriers

[00117] The materials described here, in this patent application, can be applied to reduce or prevent the formation of adhesions after surgical procedures, for example to prevent adhesion of brain tissue to the cranial vault after brain surgery or implantation of devices for prevent peritoneal adhesion.

E. Other applications

[00118] The compositions can also be used to coat tools, such as surgical instruments, for example forceps or retractors, to enhance the ability of the tools to manipulate objects. The materials can also be used here, in this patent application, they can also be used in industrial applications where it is useful to have a degradable adhesive that is biocompatible, for example to reduce the potential toxicity of degradation products, such as marine applications, for example in underwater use or connection to the surface of boats. The materials can also be used to produce objects modeled by a variety of techniques known in the art, including 3D printing. The modeled object can have micro or nano scale resolution.

[00119] The present invention will now be illustrated, but in no way limited, by way of reference to the following examples.

EXAMPLES

[00120] The following general protocol was initially applied to synthesize polyglycerol sebacate (PGS) prepolymer: 1. Equimolar amounts of glycerol and sebacic acid were weighed out. 2. The temperature of the reaction mixture was adjusted between 120 and 130 °C until the monomers were completely melted. 3. After melting the reagents, the bath or reaction temperature was reduced to the target value of 120oC and stirring was started. 4. The air inside the flask was replaced with nitrogen using three vacuum/purge cycles. 5. The reaction was followed for 8 hours. 6. The nitrogen supply was then removed and the pressure was reduced using a vacuum pump set to a target of 15 mBars.

[00121] The reaction was followed until the target molecular weight (about 3000 Da) and polydispersity (<3) were reached. The target glycerol:sebacid acid molar ratio was 1:1. The PGS prepolymer obtained was activated by reacting PGS with acryloyl chloride in the presence of TEA, followed by purification through filtration or washing with water.

[00122] The obtained PGS polymers can be acrylated but a high variability in the evolution of the molecular weight during the synthesis and storage of PGSA was observed. The root cause for the instability can be attributed to the instability of the anhydride.

[00123] One month term stability studies of 50% w/w solutions of activated prepolymer in DCM revealed continued molecular weight progression even under storage conditions at -18°C. A FTIR band at 1810 cm -1 and NMR triplets at 2.4 and 2.5 ppm were detected and attributed to anhydride by-products formed by the reaction of acryloyl chloride and free carboxylic acids. The intensity of the triplets decreased over time during storage and therefore can be linked to a 50% wt/wt molecular weight evolution of PGSA. 1. PGS prepolymer was synthesized as described above. 2. Overnight acrylation of PGS prepolymer with AcCl (0.8 mL per 5 grams of polymer) in 10% wt/vol DCM in the presence of DMAP (1 mg per gram of polymer), TEA (1.4 mL per 5 grams of polymer) and 200 ppm BHT. The amounts of AcCl and TEA can be adjusted to obtain different degrees of acylation. 3. Ethanol capping at 40°C during synthesis to eliminate anhydrides and prevent molecular weight growth during synthesis and storage. A volume ratio of ethanol to DCM of 1:5 was used. 4. Partial evaporation of ethanol and DCM. 5. Purification by washing with water. 6. Addition of 400 ppm of BHT. 7. Partial evaporation of solvents to achieve a 50% w/w solution in DCM followed by addition of 200 ppm MEHQ and storage at 4°C. 8. Incorporation of Irgacure 2959 (2-Hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone or Irgacure 651 (2,2-Dimethoxy-1,2-diphenylethan-1-one) or Irgacure TPO (oxide diphenyl(2,4,6-trimethylbenzoyl)phosphine) and solvent removal by supercritical CO2.

[00124] Where anhydrides were eliminated during synthesis, as confirmed by the decrease in bands associated with anhydrides in FTIR and NMR, it was observed that ethanol capping led to a decrease in the degree of PGSA acrylation, probably due to the cleavage of acrylate anhydride leading to the release of acrylic acid and ethyl acrylate removed during purification steps / supercritical CO2.

[00125] With reference to stability, limited evolution in molecular weight was observed for the product stored in solution at 50% wt / wt at -20°C. For the dry product, limited molecular weight changes were observed after 12 months when stored at -20°C and the product appeared stable. Molecular weight was determined by Gel Permeation Chromatography using equipment with the following specifications:

[00126] The GPC equipment used had the following specifications: Column - LT6000L, (300 x 8) mm, 10 μm equipped with a CLM3008 pre-column (10 x 4.6) mm Flow rate - 1.0 mL/ min Injection volume - 100 μL Column temperature - 35°C Refractometer temperature - 35°C Elutriation mode - Isocratic Mobile phase - Tetrahydrofuran (THF)

Example 1: Explosion Performance Test - Examples A and B

[00127] Several stable polymers, without anhydrides, were then evaluated in a burst model to determine their ability to seal vascular defects. In all cases, PGSA was used starting from PGS with molecular weight ~3000 Da manufactured according to the method described above.

[00128] The bursting performance of PGSA was evaluated for sealing a 6 mm diameter ePTFE graft sutured to the porcine carotid artery. Prior to glue application, the suture line began to leak at about 10 mmHg. Approximately 0.2 mL of PGSA was applied around the suture line using a syringe and the formulation was light cured for approximately 1 minute. Bursting performance is enhanced and the pressure at which the suture line begins to leak is measured. Burst values above 150 mmHg could be obtained.

[00129] The viscosity of the initial prepolymer was a key parameter for the burst performance of PGSA. The viscosity of the PGSA was dependent on the degree of acrylation and the application temperature as summarized in the table below:

[00130] The polymers in examples A and B have equivalent weight average molecular weights.

[00131] Viscosity analysis was performed using a Brookfield DV-II + Pro viscometer with a 2.2 mL chamber and SC4-14 spindle. The speed during the analysis was varied from 5 to 80 rpm.

[00132] Both formulations A and B contained Irgacure 2959 as a photoinitiator and were activated by light using an Omnicure S100 equipped with a 320 to 390 nm filter, 70% intensity with borosilicate tip.

[00133] Formulations with the above degrees of acrylation were tested at different temperatures and demonstrated better burst performance than Fibrin in sealing 2 mm longitudinal incisions against porcine carotid arteries. The results are shown in Figure 1.

[00134] Example A had low spreading ability at room temperature which was improved by heating the product to 37oC (decreasing viscosity) along with enhanced burst performance. Example B had good spreadability at room temperature (lower viscosity with higher degree of acrylation) with enhanced burst performance. In general, significantly improved burst performance was obtained for both examples compared to commercially used Fibrin.

[00135] PGSA also showed better burst performance against ePTFE substrates than vascular tissue. The burst pressures of Examples A and B in sealing a 2 mm longitudinal incision in ePTFE are shown in Figure 2. The maximum force that could be obtained in this configuration was ~300 mmHg as intact ePTFE begins to leak at this time. pressure.

[00136] PGSA has also demonstrated good burst performance in ePTFE vascular grafts as an adjunct to sutures. The bursting performance of PGSA was evaluated to seal a 5 mm diameter ePTFE graft sutured to the porcine carotid artery. Prior to glue application, the suture line begins to leak at approximately 10 mmHg. After application of PGSA, bursting performance is enhanced and the suture line begins to leak at the pressures shown in Figure 3.

[00137] Efficacy was validated in vivo in a sheep animal model of femoral artery graft with successful results as shown in Figure 4.

[00138] In general, as well as excellent stability, PGSA without anhydrides showed sufficient performance to be used as an adjunct to sutures in ePTFE vascular grafts.

Example 2: Burst performance of PGSA formulation according to the Invention with different photoinitiator systems

[00139] An explosion test was conducted to evaluate the sealing capacity of different formulations comprising different photoinitiator systems (example B, C and D) on ePTFE-vessel vessel anastomosis created by suture. A smaller number of sutures (8 to 10 running sutures) were used corresponding to conditions that would normally be employed by a surgeon to ensure suture line leakage. Formulations B, C and D have equivalent weight average molecular weight and degrees of acrylation (ie 0.5). The test sealant was applied along the suture line and cured with light as specified in the table below. CQ/EDB = camphorquinone / Ethyl-4-dimethylamino benzoate

[00140] Water was pumped into the vessel at a rate of 80 mL/min. The burst strength for the different formulations was recorded as the maximum pressure reached during the test. The results are reported in Figure 5. In general, equivalent burst performances were found regardless of the photoinitiator/light source system used. Of note, the CQ/EDB formulation demonstrated strong sensitivity to ambient light, whereas the other formulations can be easily handled under ambient light without visible gelling/crosslinking for a minimum of 15 minutes.

Example 3: Biocompatibility

[00141] PGSA with a degree of acrylation of ~0.45 mol/mol of glycerol and a weight average molecular weight of ~5,000 Da, was evaluated for biocompatibility, according to ISO 10993 (including cytotoxicity, Inflammatory reaction, Genotoxicity, hemocompatibility, biodegradation). In clinical dosage, no biocompatibility problem was identified.

Example 4: Performance and Biocompatibility in bone

[00142] A wide range of barrier materials have been used in guided bone regeneration. Despite being used in clinical practice, these materials still suffer from limitations, namely the need for surgical excision (non-resorbable materials), premature resorption and batch-to-batch variability (resorbable materials of natural origin).

[00143] PGSA has interesting properties to be applied as a moldable barrier in guided bone repair, which include its viscosity before polymerization (easily moldable), hydrophobicity (not easily washed off in wet environments), and rapid polymerization under demand (promoting attachment to the substrate). These properties make it ideal for sealing wet tissues, even in anatomical sites that are difficult to access.

[00144] The adhesion of PGSA to the bone was evaluated through mechanical tests and revealed interesting adhesion. In order to investigate aspects of biocompatibility, PGSA membranes of the Invention were implanted as a barrier between the periosteum and mouse bone defects of non-crucial sizes filled with a fibrin hydrogel (to prevent invagination of the membrane into the defect). . The ingrowth of the bones in these defects was then compared by microcomputed tomography with one of the defects filled with fibrin glue alone or with fibrin glue plus PTFE membranes. No complications after surgery, infection, changes in body weight, animal behavior, or general health problems were observed for the 4 weeks of implantation. In all groups, tissue healing was uneventful. At 4 weeks, new bone formation was similar in all groups (PGSA 4.7 ± 1.18 mm3, isolated fibrin 4.6 ± 0.27 mm3 and PTFE: 5.1 ± 2.32 mm3) establishing the good biocompatibility of PGSA membranes and supporting the use of the material of the invention in bone repair applications. These results are reported in Figure 6 (the top image is a 3D representation of the calvaria defect at week 0; the bottom left image is a 3D tomodensitometric reconstruction of the calvaria defect at week 0 and best week 4; the bottom right image is a graph representing the volume of new bone formation in a calvarial defect filled with either fibrin alone, fibrin and ePTFE membrane, or fibrin and PGSA membrane).

Example 5: Incorporation of coloring agent

[00145] For some applications it may be desirable to have colored material. The feasibility of incorporating a coloring agent during the manufacture of the PGSA sealant of the Invention was evaluated. FD&C 1 was used as the test agent. PGSA containing FD&C 1 was prepared according to the following steps: 1. FD&C 1 solution was prepared by mixing 0.2 g of FD&C 1 in 25 ml of Ethanol. 2. The solution was stirred and filtered (0.2 µm pores). 3. 3 μl of this solution (24 pg of Erioglaucine) was added per gram of PGSA solution (50% wt/wt in dichloromet) 4. The solution was purified and solvents removed using supercritical carbon dioxide processing .

[00146] After extraction with supercritical CO2, the final concentration of FD&C 1 in the final product is ~50 ppm. This amount allowed to achieve a blue color sealant that maintains its transparency properties, while allowing better visualization once applied to the target substrate. Therefore, it was demonstrated that the incorporation of a coloring agent does not affect the polymerization kinetics or the sealing properties of PGSA.

Example 6: Polymerization using redox agent

[00147] The feasibility of polymerizing the PGSA of the Invention in the presence of redox agents was evaluated. In summary, the following methodology was followed: 1. Target amounts of Reducer and Oxidant were obtained and ground if possible (or solubilized if necessary). 2. 0.5 g PGSA was heated at 37°C for 15 min s. 3. PGSA was mixed with the target amount of Oxidizer, then mixed with Reducer. 4. Polymerization was evaluated macroscopically

[00148] The results obtained are summarized in the table below.

[00149] The concentrations reported in the table are in relation to the dry weight of the PGSA.

Example 7: Use in drug delivery

[00150] The feasibility of releasing small molecules from photocured cured PGSA (405 nm LED, ~100 mW/cm2) was evaluated. The model molecule hydrochlorothiazide was used for this study. 7.1. First, different techniques were used to incorporate the drug into the polymer: 1. Incorporation through manual mixing of the drug crystals with PGSA preheated to 37oC 2. Incorporation through the use of solvents, followed by evaporation of the solvents

[00151] Polymerized PGSA disks of defined size and drug loading were prepared. The drug release profile was evaluated after disc immersion in PBS at 37oC and under agitation. The supernatant was removed at specified time points and the concentration of released drug was measured using UV/Vis spectroscopy.

[00152] The techniques used to incorporate the drug into the polymer did not appear to have a major impact on the observed release profile. 7.2. Next, different strategies were tested to adjust the release profile of the encapsulated drug 1. Modification in the geometry of the polymer discs:

[00153] For a PGSA disk of the Invention of 6 mm in diameter, the release profile can be adjusted by modifying the thickness of the disk, as reported in Figure 7. Example F represents a 200 μm thick disk (n=4 ), Example G represents a 400 μm thick disc (n=4), Example H represents a 800 μm thick disc (n=6). Thicker disks lead to a slower release profile. 2. Modification in the degree of acrylation of the polymer:

[00154] The use of the PGSA of the Invention with different specifications allows adjusting the drug release profile. This was demonstrated by preparing a range of PGSA derivatives with different degrees of acrylation which were used to encapsulate hydrochlorothiazide under equivalent conditions. Increasing the degree of acrylation results in slower release profiles. The results are reported in Figure 8. The degree of acylation (mol/mol of glycerol) is shown in the table below:

Example 8: 3D printing

[00155] The PGSA of the invention was 3D printed using a commercially available Autodesk Ember 3D printer equipped with a 405 nm LED using the Direct Light Processing (DLP) method. The 3D printer was custom modified to allow the use of small volumes of PGSA, and the viscous liquid PGSA was preheated to ~100oC to decrease its viscosity. Furthermore, PGSA was doped with a UV blocking compound (Mayzo OB+) to control the light scattering properties.

[00156] Under these conditions, the following printing parameters were evaluated as preferred: -continuation

[00157] Structures with micrometer scale resolution can be printed, as detailed in Figure 9.

Example 9:

[00158] The performance of the PGSA of the Invention was compared with a commercially available sealant (glutaraldehyde (BSAG)) in an in vivo porcine model for sutureless closure of vascular incisions.

[00159] 2 mm defects of the carotid artery (CA) and jugular vein were created and closed with the PGSA of the Invention or bovine serum albumin and glutaraldehyde (BSAG) without the use of sutures.

[00160] These experiments demonstrated that the PGSA of the Invention effectively sealed vessel defects and showed no signs of stenosis and showed low inflammatory reaction in contrast to BSAG.

Claims (15)

1. Composition comprising: a prepolymer comprising a polymeric unit of general formula (-AB-)n, wherein A represents a substituted or unsubstituted ester, B represents a substituted or unsubstituted acid ester comprising at least two ester functions acid, and in which the prepolymer has a portion derived from a polyol and a fraction derived from a polyacid, characterized in that the prepolymer has the general formula (I): where pen each individually represents an integer equal to or greater than 1; where R6 and R6' in each individual unit are independent and can be a polymeric chain or R6 and R6' in each individual unit are independent and can be - C(=O)-CR3=CR4R5, where R3, R4, R5 are independently of one another selected from the group consisting of H, alkyl, aryl, substituted alkyl, substituted aryl, carboxylic acid, ester, amide, amine, urethane, ether and carbonyl; or R6 and R6' on each individual unit are independent and can be H, alkyl, aryl, heterocycles, cycloalkyl, aromatic heterocycles, multicycloalkyl, ester, ether, halide, carboxylic acid, amino, alkylamino, dialkylamino, trialkylamino, amido, carbamoyl, thioether, thiol, alloxy or ureido groups; wherein R7 is selected from the group consisting of alkyl, aryl, substituted alkyl, substituted aryl, amine, urethane, thiol or thio ester; and wherein the content of grafted anhydrides in the composition is less than 0.05 mol/mol polyacid. 2. Composition according to claim 1, characterized by the fact that the composition does not comprise anhydride. 3. Composition, according to claim 1 or 2, characterized by the fact that p is from 4 to 10. 4. Composition according to any one of claims 1 to 3, characterized in that R6 and R6' are 5. Composition according to any one of claims 1 to 4, characterized in that the prepolymer has a degree of activation between 0.25 and 0.8 mol/mol of polyacid, and optionally comprising a photoinitiator . 6. Composition according to claim 5, characterized in that the prepolymer has an activation degree of 0.5 mol/mol of polyacid. 7. Composition according to any one of claims 1 to 5, characterized in that R7 is -CH2CH3. 8. Method for manufacturing a composition, as defined in any one of claims 1 to 5, characterized in that it comprises: (i) polycondensing a first component comprising two or more functionalities of the general formula —OR, where R of each group is independently hydrogen or alkyl; and a second component comprising two or more acid ester functionalities; (ii) activating the prepolymer produced by step (i); (iii) controlling the anhydride content; optionally (iv) blocking free hydroxyl groups; and/or optionally, (v) purifying the activated prepolymer produced by steps (ii) and/or (iii) and/or (iv). 9. Method according to claim 8, characterized in that the first component comprises glycerol, and/or the second component comprises sebacic acid. 10. Method according to claim 8 or 9, characterized in that the activating agent is an acrylating agent. 11. Method according to any one of claims 8 to 10, characterized in that anhydrides are removed through reaction with a nucleophile. 12. Method according to claim 11, characterized in that the nucleophile comprises ethanol. 13. Method according to any one of claims 8 to 12, characterized in that the purification comprises filtering and/or washing with salt water; or wherein step (iv) comprises acylation. 14. Method of curing the composition, as defined in any one of claims 1 to 7, or a composition produced by the method, as defined in any one of claims 8 to 13, characterized in that it comprises curing the composition with light in the presence of a photoinitiator. 15. Cured composition, characterized by the fact that it is obtainable by the method, as defined in claim 14.