Polymerizable compositions and methods of using the same to form adhesive materials and applications thereof

Abstract

The present application belongs to the technical field of materials, and more particularly, relates to a polymerizable composition, a preparation method thereof and application of the polymerizable composition in biomedical adhesion materials for bonding tissues. The polymerizable composition of the present application can form an adhesion material through branched polymerization, has a fast polymerization rate and a high monomer conversion rate, and is simple to prepare, and can be widely applied to, for example, in-situ polymerization and surface-initiated polymerization, thereby improving the practicability of cyanoacrylate and forming a more ideal adhesion material.

Description

[0001] Cross-references

[0002] This application claims priority to U.S. Provisional Application No. 63 / 346,330, filed May 27, 2022, the entire contents of which, including any forms, figures or drawings, are incorporated herein by reference. Technical Field

[0003] This invention belongs to the field of materials science, and more specifically, this invention relates to a polymerizable composition, a method for forming an adhesive material using the polymerizable composition, and the use of the polymerizable composition in the preparation of adhesive materials for adhesive tissues. Background Technology

[0004] Cyanoacrylates are highly reactive monomers whose anionic polymerization is spontaneously initiated by nucleophiles (such as water, amines, and bases), exhibiting rapid polymerization rates and high monomer conversion rates, and requiring no strict adherence to the demanding reaction conditions of most polymerization methods. However, due to the lack of control over the polymerization, the resulting linear chain polymers have uneven molecular weights. This high monomer reactivity severely limits the synthetic progress of cyanoacrylate polymerization. Recent methods, by using inhibitors to control the reaction of this highly reactive monomer, have enabled the synthesis of other polymer topologies. However, these methods still have some drawbacks, such as demanding reaction conditions (e.g., inert atmospheres, metal catalysis, heating, or ultraviolet irradiation), slow polymerization rates, and the need for post-polymerization purification or reprocessing.

[0005] However, the high monomer reactivity is a major reason for the widespread use of cyanoacrylates, especially as a fast-acting hemostatic adhesive, where polymerization is initiated by nucleophiles on the surface, forming covalent bonds between the surface and the polymerized adhesive film. Therefore, most existing polymerization methods for cyanoacrylates are considered unsuitable or ineffective in many well-known applications in repair, interior decoration, manufacturing, and biomedicine. Given the growing demand for new features for advanced applications, the choice of polymerization methods must be expanded to synthesize other polymer topologies without sacrificing practicality.

[0006] Medical adhesives have been developed as a practical alternative to sutures and staplers for reconnecting tissue edges to close wounds and stop bleeding. The use of medical adhesives can reduce postoperative pain and alleviate intraoperative and postoperative complications due to their ease of use, good sealing properties, and non-toxicity.

[0007] Cyanoacrylate is one of the most common medical adhesives, capable of quickly and effectively bonding various surfaces, hence its nickname "super glue." Despite its popularity in clinical use, cyanoacrylate still has several drawbacks, one of which is the mismatch between the mechanical properties of the polymerized film and soft tissue. Reducing this difference minimizes the risk of adhesive failure and avoids postoperative discomfort and complications caused by restricted tissue movement due to this discrepancy. Existing techniques for addressing this issue primarily involve modifying cyanoacrylate, for example, through solution polymerization, inert reaction conditions, metal catalysis, heating, and ultraviolet irradiation; however, these modifications diminish the practical advantages of cyanoacrylate.

[0008] Therefore, based on the problems existing in the prior art, there is an urgent need in the art for a polymerizable composition that can form an adhesive material through polymerization including branching polymerization, wherein the polymerizable composition has a fast polymerization rate and a high monomer conversion rate, and does not require restrictive or harsh reaction conditions. Summary of the Invention

[0009] As mentioned above, existing polymerization methods for cyanoacrylates suffer from drawbacks such as a lack of control over the polymerization process and the need for restrictive or harsh reaction conditions, which greatly limit their application in various fields. Therefore, there is an urgent need in the art for a polymerizable composition that can form other polymer topologies through polymerization, including branching polymerization, thereby creating a more ideal adhesive material and improving the practicality of cyanoacrylates.

[0010] Therefore, in a first aspect, the present invention provides a polymerizable composition comprising:

[0011] (i) at least one chain-grown polymerizable monomer containing cyanoacrylate and / or a chain-grown polymerizable macromonomer;

[0012] (ii) at least one chain-grown polymerizable comonomer comprising at least one carboxylic acid moiety and at least one cyanoacrylate functional group and / or a chain-grown polymerizable comacromonomer; and

[0013] (iii) Optionally one or more bifunctional or polyfunctional monomers comprising multiple cyanoacrylates.

[0014] In a second aspect, the present invention provides a method for forming an adhesive material, the method comprising:

[0015] 1) Provide a polymerizable composition according to a first aspect of the invention, wherein the polymerizable composition is in fluid form; and

[0016] 2) To form the adhesive material by contacting the polymerizable composition with one or more nucleophiles to initiate polymerization, including branching polymerization, within the polymerizable composition.

[0017] In a third aspect, the present invention provides the use of the polymerizable composition described in the first aspect of the present invention in the preparation of adhesive materials.

[0018] The polymerizable compositions of the present invention can be polymerized to form adhesive materials through polymerization including branched polymerization. The polymerizable compositions have fast polymerization rates and high monomer conversion rates, and do not require restrictive or harsh reaction conditions. Therefore, they can be widely used in, for example, in-situ polymerization and surface-initiated polymerization, thereby improving the practicality of cyanoacrylates and forming more ideal adhesive materials. Attached Figure Description

[0019] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other implementation schemes can be obtained based on these drawings without creative effort.

[0020] Figure 1 This is a schematic diagram of a representative reaction of branched anionic polymerization. In this reaction, monomer (1) and comonomer (2) undergo simultaneous copolymerization and chain transfer reactions to form a branched polymer.

[0021] Figure 2 Size exclusion chromatography (SEC) chromatograms of the polymers shown in samples 1-7 of Table 1 using tetrahydrofuran as the mobile phase are displayed. Detailed Implementation

[0022] The present invention will now be clearly and completely described in conjunction with its embodiments and accompanying drawings. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. All other embodiments that can be obtained by those skilled in the art based on the embodiments of the present invention are within the scope of protection of the present invention.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter pertains.

[0024] As mentioned above, due to the high reactivity of cyanoacrylates, existing synthesis methods require stringent reaction conditions, which undermines the practical advantages of cyanoacrylates and greatly limits their application.

[0025] The inventors have discovered that by adding a comonomer comprising cyanoacrylate and at least one chain transfer functional group to a polymerizable composition, the comonomer can rapidly initiate branching polymerization of the polymerizable composition without the need for restrictive or harsh reaction conditions. This polymerization reaction is also applicable to the spontaneous generation of branching caused by chain transfer during the polymerization reaction, whereby at least one chain transfer functional group of the comonomer is deprotonated in the chain transfer reaction, thereby generating at least one chain growth site and transforming the comonomer into a branched linker. Therefore, polymerizable compositions containing the above-mentioned comonomer can be polymerized to form adhesive materials through polymerization, including branching polymerization, which has a fast polymerization rate and high monomer conversion rate, and does not require restrictive or harsh reaction conditions, thus enabling applications such as in-situ polymerization and surface-initiated polymerization.

[0026] Therefore, in a first aspect, the present invention provides a polymerizable composition comprising:

[0027] (i) at least one chain-grown polymerizable monomer containing cyanoacrylate and / or a chain-grown polymerizable macromonomer;

[0028] (ii) at least one chain-grown polymerizable comonomer comprising at least one carboxylic acid moiety and at least one cyanoacrylate functional group and / or a chain-grown polymerizable comacromonomer; and

[0029] (iii) Optionally one or more bifunctional or polyfunctional monomers comprising multiple cyanoacrylates.

[0030] Embodiments of the present invention relate to the branching polymerization of polymerizable compositions based on addition reactions in chain-growth polymerization of comonomers and deprotonation reactions in chain transfer reactions, by means of which the comonomers can be transformed into branching linkages. By including comonomers with chain transfer functional groups in the polymerizable composition, the resulting polymer material can obtain a polymer topology different from that obtained from the same composition without such comonomers. The polymerizable compositions of the present invention do not involve complex reaction mechanisms, such as systems requiring free radical polymerization or restrictive or harsh conditions (e.g., inert atmospheres, metal catalysis, heating, or ultraviolet radiation), to form branched polymer chains formed during anionic polymerization.

[0031] As is known to those skilled in the art, the term "chain transfer reaction" refers to the process by which an active chain radical transfers unpaired electrons to other molecules in a polymer reaction system, generating macromolecules and new radicals. In a chain transfer reaction, a polymer chain-terminal radical attacks a molecule containing a weak bond, capturing one atom. The active chain-terminal radical is eventually terminated, while a new radical forms at the weak bond site. Depending on the reactivity of the transferred radical, it may continue to initiate monomer polymerization or it may fail to do so. Chain transfer reactions are one of the important elementary reactions in radical polymerization, significantly influencing the molecular weight and polymerization rate of the polymer products.

[0032] The polymerizable compositions of the present invention are characterized by a chain transfer reaction that provides in-situ branching throughout the final polymer material. Specifically, the polymerizable compositions are formulated such that the chain transfer portion can initiate a polymerization reaction with the active anionic chain ends of the growing polymer chains. Branching can be formed from the chain transfer functional groups (i.e., the carboxylic acid moiety) in the comonomer when the comonomer already incorporated along the chain is deprotonated to subsequently generate new chain growth sites, or when the deprotonated carboxylic acid moiety of the comonomer is incorporated along the growing chain before or after initiating the polymerization of a new chain therewith. The chain transfer sites used to initiate branching formation can be functional groups on the side groups of any other growing or non-growing chains in the resulting polymer material.

[0033] The polymerizable compositions encompass a range from relatively non-viscous liquids with relatively few or no macromonomers to medium-viscosity, easily flowing liquids with a relatively high content of macromonomers. Typically, all components of the polymerizable compositions are capable of participating in branched polymerization at fast polymerization rates and high monomer conversion rates, without requiring restrictive or harsh reaction conditions.

[0034] In one embodiment of the present invention, the chain-growing polymerizable monomer comprising cyanoacrylate and / or the chain-growing polymerizable macromonomer may be one or more monocyanoacrylates. In a preferred embodiment of the present invention, the monocyanoacrylate is a 2-cyanoacrylate without a carboxylic acid moiety, including but not limited to: n-butyl cyanoacrylate, n-hexyl cyanoacrylate, 2-octyl cyanoacrylate, butoxyethyl cyanoacrylate, hexoxyethyl cyanoacrylate, poly(ethylene glycol) cyanoacrylate, poly(lactic acid) cyanoacrylate, poly(glycolic acid) cyanoacrylate, poly(ε-caprolactone) cyanoacrylate, poly(4-hydroxybutyrate) cyanoacrylate, poly(3-hydroxyoctanoate) cyanoacrylate, poly(glycerol sebate) cyanoacrylate, poly(trimethylene carbonate) cyanoacrylate, and combinations thereof. In a preferred embodiment of the present invention, the chain-growing polymerizable monomer containing cyanoacrylate and / or the chain-growing polymerizable macromonomer is a low molecular weight reactive monomer, such as n-butyl cyanoacrylate, n-hexyl cyanoacrylate or 2-octyl cyanoacrylate.

[0035] In one embodiment of the present invention, the chain-growing polymerizable comonomer and / or chain-growing polymerizable comazomonomer may be a carboxyl-functionalized ester of 2-cyanoacrylate, the structure of which is shown in formula (1):

[0036] R 1 (CR 2 R 3 ) x O(O)CC(CN)=CH2 (1)

[0037] Where x is from 1 to 12, and R 1 R 2 and R 3 Independently, it is H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted phenyl, optionally substituted phenoxy, -C(O)OR 4 -C(O)NR 4 R 5 Or -O(O)CCC(CN)=CH2, and wherein the optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted phenyl, or optionally substituted phenoxy is replaced by a C1-C8 alkyl, C1-C8 alkoxy, phenyl, phenoxy, -C(O)OH, -C(O)OR 4 -C(O)NR 4 R 5 Or -O(O)CCC(CN)=CH2 replaces one or more times, where R 4 and R 5Independently H, C1-C8 alkyl or phenyl, wherein R 1 R 2 and R 3 At least one of them contains -C(O)OH.

[0038] The chain-growing polymerizable comonomer and / or chain-growing polymerizable copolymer macromonomer act as "chain transfer agents" in the branching polymerization method to generate polymer branches in situ during the polymerization reaction. The chain transfer reaction deprotonates the carboxylic acid functional group of the chain-growing polymerizable comonomer, thereby forming a conjugate base within the molecule. This carboxylic acid conjugate base is added to the cyanoacrylate functional group to initiate a new growing polymer chain. If the cyanoacrylate functional group of the comonomer has already been incorporated into the polymer chain, the new growing polymer chain produces newly formed branches. If the cyanoacrylate functional group of the comonomer has not yet been incorporated into the polymer chain, then when the cyanoacrylate functional group from the comonomer is incorporated into the polymer chain, the new growing polymer chain becomes a branch.

[0039] In one embodiment, the carboxyl-functionalized ester of 2-cyanoacrylate can be a carboxyl-terminated ester of 2-cyanoacrylate, with the structure shown in formula (2):

[0040] HO(O)C(CH2) y OC(O)C(CN)=CH2 (2)

[0041] Where y ranges from 2 to 12.

[0042] In a specific implementation, y can be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0043] In an optional embodiment of the invention, the polymerizable composition may further comprise one or more bifunctional or multifunctional macromonomers comprising multiple cyanoacrylates, which are dicyanoacrylates or polycyanoacrylates for forming branching and / or crosslinking sites. The bifunctional or multifunctional macromonomers comprising multiple cyanoacrylates include, but are not limited to: poly(ethylene glycol) dicyanoacrylate, poly(lactic acid) dicyanoacrylate, poly(glycolic acid) dicyanoacrylate, poly(ε-caprolactone) dicyanoacrylate, poly(4-hydroxybutyrate) dicyanoacrylate, poly(3-hydroxyoctanoate) dicyanoacrylate, poly(glycerol sebate) dicyanoacrylate, poly(trimethylene carbonate) dicyanoacrylate, and combinations thereof. The inclusion of the dicyanoacrylates or polycyanoacrylates and their proportions allow those skilled in the art to obtain the desired viscosity of the adhesive composition and a material having the desired properties after polymerization.

[0044] In this invention, the ratio of (i) a chain-growing polymerizable monomer and / or a chain-growing polymerizable macromonomer comprising cyanoacrylate in the polymerizable composition to (ii) a chain-growing polymerizable comonomer and / or a chain-growing polymerizable copolymer comprising at least one carboxylic acid moiety and at least one cyanoacrylate functional group can affect the number-average molar mass of the final polymer obtained. A higher ratio of (ii) a chain-growing polymerizable comonomer and / or a chain-growing polymerizable copolymer comprising at least one carboxylic acid moiety and at least one cyanoacrylate functional group results in a lower number-average molar mass of the obtained polymer. Those skilled in the art can select any ratio as needed to obtain a material with desired properties during polymerization. In some embodiments, the molar ratio of (i) the polymerizable monomer to (ii) the comonomer is from 250:25 to 250:1, for example, 250:25, 250:22, 250:20, 250:18, 250:15, 250:12, 250:10, 250:9, 250:8, 250:7, 250:6, 250:5, 250:4, 250:3, 250:2, 250:1, or any molar ratio therebetween. In a preferred embodiment, the molar ratio of (i) the polymerizable monomer to (ii) the comonomer is from 250:20 to 250:3.

[0045] In embodiments of the invention, the polymerizable composition may further comprise a filler that is not an initiator for chain growth polymerization. The filler may be glass, plastic, metal, ceramic, or any other material that does not react with the polymerizable composition. The filler may be soluble or insoluble, but must be small enough that the polymerizable composition is a suspension.

[0046] In a second aspect, the present invention provides a method for forming an adhesive material, the method comprising:

[0047] 1) Provide a polymerizable composition according to a first aspect of the invention, wherein the polymerizable composition is in fluid form; and

[0048] 2) To form the adhesive material by contacting the polymerizable composition with one or more nucleophiles to initiate polymerization, including branching polymerization, within the polymerizable composition.

[0049] In embodiments of the invention, the polymerizable composition is in fluid form (e.g., a fluid with acceptable viscosity) and can be used as an adhesive composition that, upon contact with one or more nucleophiles on one or more surfaces, initiates a rapid polymerization reaction to form a film bonded to one or more surfaces via one or more covalent bonds. The polymerizable composition contains a carboxylic acid moiety that allows for chain transfer reactions during polymerization and generates polymer branches during chain growth between initiation and termination reactions. Due to branching and crosslinking, the resulting strongly adhesive material has numerous sites for attachment to the surface. The surfaces include glass, metals, plastics, biological tissues, and similar materials. In one embodiment of the invention, the surface is a biological tissue surface, such as the tissue surface of a human, animal, or plant, including but not limited to epithelial tissue surfaces (e.g., skin surfaces, mucous membrane surfaces), connective tissue surfaces, muscle tissue surfaces, etc.

[0050] In this document, the nucleophile is an initiator for polymerization of the polymerizable compositions of the present invention, and may include water, small or large molecules containing hydroxyl, carboxylic acid, and / or other functional groups, and may be in the form of a base. In one embodiment of the invention, the nucleophile is a conjugate base of water, carboxylic acid, or amine. In one embodiment of the invention, the nucleophile is on or part of a surface. For example, but not limitingly, a conjugate base of water or other functional groups on the surface to be bonded may initiate anionic polymerization of cyanoacrylate functional groups in the polymerizable compositions of the present invention. The nucleophile may be added or inherent to the surface, such as functional groups on or within biological tissue surfaces, including water, proteins, sugars, or lipids.

[0051] In one embodiment of the invention, the polymerizable composition can be applied to the surface, whereby an adhesive material is rapidly formed on the surface when the substantially anhydrous polymerizable composition of the invention is placed on the surface to initiate chain-growth polymerization. The polymerizable composition further undergoes protonation of the growing poly(cyanoacrylate) chains to form conjugate bases of the carboxylic acid functional groups of the comonomer, wherein these conjugate bases of the carboxylic acid functional groups are added to the cyanoacrylate functional groups within the polymerizable composition to initiate new growing polymer chains. Because the comonomer contains cyanoacrylate functional groups, these new growing polymer chains may have already been incorporated into another polymer chain or may ultimately be incorporated into another polymer chain, thus becoming new branches.

[0052] In embodiments of the invention, the polymerizable composition is a fluid with an acceptable viscosity that readily flows onto the surface of biological tissue. In one embodiment of the invention, the polymerizable composition can be administered via a tube, syringe, or any container that isolates the polymerizable composition from air or any moisture- or alkaline medium until it comes into contact with the target tissue surface.

[0053] Those skilled in the art will understand that the descriptions above relating to the polymerizable compositions of the first aspect of the present invention are applicable to the second aspect of the present invention, and therefore will not be repeated here.

[0054] In a third aspect, the present invention provides the use of the polymerizable composition described in the first aspect of the present invention in the preparation of adhesive materials.

[0055] The adhesive material can be used to bond the surfaces of various materials, including, for example, glass, metal, plastic, biological tissue, and similar materials. In one embodiment of the invention, the surface is the surface of biological tissue, such as the surface of human, animal, or plant tissue, including but not limited to epithelial tissue surfaces (such as skin surfaces, mucous membrane surfaces), connective tissue surfaces, muscle tissue surfaces, etc. It is understood that, in this case, the monomers or macromonomers used in the invention are preferably biocompatible.

[0056] Similarly, the descriptions above relating to the polymerizable composition of the first aspect and the adhesive material of the second aspect are applicable to the third aspect of the invention, and therefore will not be repeated here.

[0057] The following definitions are used to explain the features of the embodiments disclosed herein, and are used only to define elements of the invention.

[0058] As used herein, the term "tissue surface" refers to a tissue surface containing nucleophilic substances (e.g., hydroxyl or amino groups) that can induce adhesion of adhesive materials.

[0059] As used herein, the term “rapid” in describing the polymerization process in which a polymerizable composition is transformed from a liquid into an effective non-flowing solid refers to the time elapsed after the polymerizable composition comes into contact with the polymerization initiator, ranging from more than 0 seconds to up to about 5 minutes.

[0060] As used herein, the term "film" in describing adhesive materials refers to a solid having a main cross-sectional area much larger than the thickness defined by two perpendicular surfaces.

[0061] As used in this article, the term "growth" in describing the polymerization process refers to increasing the length of the active polymer chain by adding monomers and / or macromonomers.

[0062] Example

[0063] The present invention will now be described in detail with reference to the following embodiments and accompanying drawings. It should be understood that the following embodiments are given merely as examples to illustrate the invention and are not intended to limit the scope of the invention. The scope of protection of the invention is defined by the appended claims. Furthermore, those skilled in the art will understand that modifications can be made to the technical solutions of the invention without departing from the spirit and intent of the invention. Unless otherwise specified, the technical means used in the embodiments are conventional means well known to those skilled in the art. Unless otherwise stated, all percentages are weight percentages, and all solvent mixture ratios are molar ratios.

[0064] Example 1.2 Synthesis of carboxyl-terminated esters (chain transfer agents) of cyanoacrylic acid

[0065] To prepare the chain transfer agent, ε-caprolactone (10.0 g, 87.6 mmol) was added dropwise to an aqueous solution of NaOH (3.9 g, 96.5 mmol) (170 mL). The mixture was stirred overnight at room temperature and acidified with hydrochloric acid to pH 3. The product was extracted from the aqueous mixture with ethyl acetate (3 × 130 mL), and the extract solution was dried over anhydrous sodium sulfate and purified by column chromatography to give 6-hydroxyhexanoic acid as a colorless oil. The oil was added to a solution of benzyl bromide (26.4 g, 154.6 mmol) and triethylamine (31 mL) in dichloromethane (150 mL). The resulting mixture was washed with a saturated aqueous solution of ammonium chloride (2 × 80 mL), dried over anhydrous sodium sulfate, and purified by column chromatography to give benzyl 6-hydroxyhexanoate as a colorless liquid. The resulting product was added to 11-cyano-9,10-dihydro-9,10-ethylanthracene-11-carboxylic acid (20.3 g, 73.8 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (14.2 g, 74.1 mmol), and 4-dimethylaminopyridine (1.9 g, 15.4 mmol) dissolved in dichloromethane (2 L). The resulting solution was stirred overnight at room temperature and washed with saturated aqueous solutions of NaHCO3 (750 mL) and NaCl (750 mL) and 10% citric acid aqueous solution (750 mL). The resulting solution was dried over anhydrous sodium sulfate and purified by column chromatography to give 6-(benzyloxy)-6-oxohexyl-11-cyano-9,10-dihydro-9,10-ethylanthracene-11-carboxylic acid ester. A palladium / activated carbon catalyst (10 wt%, 3 g) was added to an ethyl acetate (600 mL) solution of the solid, and the reaction was carried out overnight at room temperature under a hydrogen atmosphere. The solution was separated from the catalyst by filtration and concentrated under vacuum to give 5-carboxypentyl-11-cyano-9,10-dihydro-9,10-ethylanthracene-11-carboxylic acid ester as a colorless oil. Finally, a mixture of this oil, maleic anhydride (23.0 g, 234.8 mmol), hydroquinone (30 mg), and phosphorus pentoxide (60 mg) in xylene (300 mL) was refluxed for 8 hours. The solution was concentrated under vacuum and dissolved three times in toluene (180 mL), and the solid was filtered off. After removing the solvent under vacuum, the residue was redeprecipitated with ethyl acetate and hexane. After removing the solvent under vacuum, 5-carboxypentyl cyanoacrylate was given.

[0066] Example 2. Preparation of poly(2-octylcyanoacrylate) with linear topology

[0067] In a representative experiment, Sample 1 (Table 1) was prepared by combining and thoroughly mixing the initiator triethylamine (0.5 μL, 3.59 μmol) and 2-octylcyanoacrylate (187.56 mg, 0.90 mmol). The initially liquid sample rapidly transformed into a polymer film. The polymer was purified by precipitating it from a dichloromethane solution into methanol and drying the precipitate overnight at 60 °C. A small portion of the sample was dissolved in CDCl3 for use... 1 1H NMR analysis. The obtained NMR spectra indicate that the polymerization reaction occurred with high conversion. The number-average molar mass (Mn) was determined by size exclusion chromatography. n,SEC The results for the molar mass dispersion (PDI) are shown in Table 1.

[0068] Example 3. Preparation of poly(2-octyl cyanoacrylate) with a branched topology (using 5-carboxypentyl cyanoacrylate as a chain transfer agent)

[0069] Representative samples, Sample 2 (Table 1), were prepared by combining and mixing 2-octyl cyanoacrylate (187.56 mg, 0.90 mmol) and 5-carboxypentyl cyanoacrylate (2.26 mg, 0.01 mmol) in vials. Triethylamine (0.5 μL, 3.59 μmol) was rapidly added to this solution as an initiator to initiate the polymerization reaction. Samples 3–7 were treated in the same manner, with the component addition ratios shown in Table 1. The initial liquid rapidly formed a polymer film. For further analysis, the polymer was purified by precipitating it from a dichloromethane solution into methanol and drying the precipitate overnight at 60 °C. A small portion of the sample was dissolved in CDCl3 for further analysis. 1 1H NMR analysis. The obtained NMR spectra indicate that the polymerization reaction occurred with high conversion. The number-average molar mass (Mn) was determined by size exclusion chromatography. n,SEC and molar mass dispersion (PDI), and the number-average molar mass (M n,SEC The molar mass dispersion (PDI) is consistent with that of the branched polymer, which is due to the reduction in hydrodynamic volume of the polymer caused by branching relative to sample 1.

[0070] Table 1. Branching polymerization of 2-octyl cyanoacrylate monomer (1) by simultaneous copolymerization and chain transfer reaction using triethylamine (3) as an initiator and 5-carboxypentyl cyanoacrylate (2).

[0071]

[0072] Results Analysis: In Sample 1, the absence of comonomers in the monomer mixture resulted in a linear polymer with a higher molecular weight compared to the branched polymer, which was in line with the inventors' expectations. Samples 2-4 showed that the molecular weight of the obtained polymers decreased with the addition of more comonomers, due to a reduction in the hydrodynamic volume of the obtained polymers, indicating that the degree of branching of the obtained polymers increased with the increase of comonomer content. Samples 5-7 showed that, compared with Samples 2-4, the molecular weight of the obtained polymers further decreased with the increase of the initiator ratio, indicating that the polymerization was controlled.

[0073] All patents, patent applications, provisional applications, and publications mentioned or cited herein, including figures and tables, are incorporated herein by reference without contradicting the express teachings of this specification.

[0074] It should be understood that the embodiments and implementations described herein are for illustrative purposes only, and various modifications or variations made based on these embodiments and implementations will be provided to those skilled in the art and will be included within the spirit and scope of the invention. Furthermore, any element or limitation of any invention or implementation thereof disclosed herein may be combined with any and / or all other elements or limitations disclosed herein (alone or in any combination) or any other invention or implementation thereof, and all such combinations are considered to be within the scope of the invention, but not limited thereto.

[0075] References

[0076] Bhagat,V.,Becker,ML,Degradable adhesives for surgery and tissue engineering,Biomacromolecules 2017,18,3009-39.

[0077] Martín-Ballestera,A.,García-Cerdáa,D.,Prieto-Mourea,B.,Martín-Martínezc JMLloris-Carsíab,JM,Use of cyanoacrylate adhesives in dermallesions:a review,Journal of Adhesion Science and Technology,2013,

[0078] Petrie,E.M.,Cyanoacrylate adhesives in surgical applications:acritical review,Rev.Adhesion Adhesives,2014,2(3),253-310.

Claims

1. A polymerizable composition comprising: (i) At least one chain-growing polymerizable monomer comprising cyanoacrylate, wherein the chain-growing polymerizable monomer comprising cyanoacrylate is one or more monocyanoacrylates; (ii) at least one chain-growing polymerizable comonomer comprising at least one carboxylic acid moiety and at least one cyanoacrylate functional group; and (iii) Optionally one or more bifunctional or polyfunctional monomers comprising two or more cyanoacrylates; The chain-growing polymerizable monomer containing cyanoacrylate does not include the chain-growing polymerizable comonomer containing at least one carboxylic acid moiety and at least one cyanoacrylate functional group; The molar ratio of the chain-growing polymerizable monomer containing cyanoacrylate to the chain-growing polymerizable comonomer containing at least one carboxylic acid moiety and at least one cyanoacrylate functional group is 250:25 to 250:

1. The polymerizable composition forms branched polymer chains during anionic polymerization.

2. The polymerizable composition according to claim 1, wherein the monocyanoacrylate is a 2-cyanoacrylate without a carboxylic acid moiety.

3. The polymerizable composition according to claim 2, wherein the 2-cyanoacrylate without the carboxylic acid portion is n-butyl cyanoacrylate, n-hexyl cyanoacrylate, 2-octyl cyanoacrylate, butoxyethyl cyanoacrylate, hexoxyethyl cyanoacrylate, poly(ethylene glycol) cyanoacrylate, poly(lactic acid) cyanoacrylate, poly(glycolic acid) cyanoacrylate, poly(α-caprolactone) cyanoacrylate, poly(4-hydroxybutyrate) cyanoacrylate, poly(3-hydroxyoctanoate) cyanoacrylate, poly(glycerol sebate) cyanoacrylate, poly(trimethylene carbonate) cyanoacrylate, or a combination thereof.

4. The polymerizable composition according to any one of claims 1-3, wherein the chain-growing polymerizable monomer comprising cyanoacrylate is n-butyl cyanoacrylate, n-hexyl cyanoacrylate, or 2-octyl cyanoacrylate.

5. The polymerizable composition according to any one of claims 1-3, wherein the chain-growing polymerizable comonomer is a carboxyl-functionalized ester of 2-cyanoacrylate, having the structure shown in formula (1): R 1 (CR 2 R 3 ) x O(O)C-C(CN)=CH2 (1) Where x is from 1 to 12, and R 1 R 2 and R 3 Independently, it is H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted phenyl, optionally substituted phenoxy, -C(O)OR 4 -C(O)NR 4 R 5 And wherein the optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted phenyl, or optionally substituted phenoxy is replaced by a C1-C8 alkyl, C1-C8 alkoxy, phenyl, phenoxy, -C(O)OH, -C(O)OR 4 -C(O)NR 4 R 5 Replace once or multiple times, where R 4 and R 5 Independently H, C1-C8 alkyl or phenyl, wherein R 1 R 2 and R 3 At least one of them contains -C(O)OH.

6. The polymerizable composition according to claim 5, wherein the carboxyl-functionalized ester of 2-cyanoacrylate is a carboxyl-terminated ester of 2-cyanoacrylate, having the structure shown in formula (2): HO(O)C(CH2) y OC(O)C(CN)=CH2 (2) Where y ranges from 2 to 12.

7. The polymerizable composition according to any one of claims 1-3, wherein the bifunctional or polyfunctional monomer comprising two or more cyanoacrylates is any polymeric diester of 2-cyanoacrylate.

8. The polymerizable composition according to claim 7, wherein any polymeric diester of said 2-cyanoacrylate is poly(ethylene glycol) dicyanoacrylate, poly(lactic acid) dicyanoacrylate, poly(glycolic acid) dicyanoacrylate, poly(α-caprolactone) dicyanoacrylate, poly(4-hydroxybutyrate) dicyanoacrylate, poly(3-hydroxyoctanoate) dicyanoacrylate, poly(glycerol sebacic acid) dicyanoacrylate, poly(trimethylene carbonate) dicyanoacrylate, or a combination thereof.

9. The polymerizable composition according to any one of claims 1-3, comprising 2-octyl cyanoacrylate and 5-carboxypentyl cyanoacrylate.

10. The polymerizable composition according to any one of claims 1-3, wherein the molar ratio of the chain-growing polymerizable monomer comprising cyanoacrylate to the chain-growing polymerizable comonomer comprising at least one carboxylic acid moiety and at least one cyanoacrylate functional group is from 250:20 to 250:

3.

11. The polymerizable composition according to any one of claims 1-3, wherein the polymerizable composition further comprises a filler.

12. The polymerizable composition of claim 11, wherein the filler is glass, plastic, metal, ceramic or any other material that does not react with the polymerizable composition.

13. The polymerizable composition according to any one of claims 1-3, wherein the chain-growing polymerizable comonomer is a chain-growing polymerizable comonomer.

14. A method for forming an adhesive material, the method comprising: 1) Providing a polymerizable composition according to any one of claims 1-13, wherein the polymerizable composition is in fluid form; and 2) To form the adhesive material by contacting the polymerizable composition with one or more nucleophiles to initiate polymerization, including branching polymerization, within the polymerizable composition.

15. The method of claim 14, wherein the nucleophile is a water or a conjugate base of a carboxylic acid or an amine.

16. The method of claim 14, wherein the nucleophile is on the surface or is part of the surface.

17. The method of claim 16, wherein the surface is a biological tissue surface.

18. The method of claim 17, wherein the biological tissue surface is the tissue surface of an animal or plant.

19. The method of claim 17, wherein the biological tissue surface is a human tissue surface.

20. Use of the polymerizable composition according to any one of claims 1-13 in the preparation of adhesive materials.

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