WO2018213433A1

WO2018213433A1 - Hydrogel medical adhesives

Info

Publication number: WO2018213433A1
Application number: PCT/US2018/032949
Authority: WO
Inventors: Bruktawit Asfaw; Fiona Carney; Dominic UGBEDAH; Sarah KOKOTOFF
Original assignee: Biocure, Inc.
Priority date: 2017-05-16
Filing date: 2018-05-16
Publication date: 2018-11-22

Abstract

Medical adhesives formed from macromers having a polymeric backbone, pendant chains bearing crosslinkable groups, and pendant groups with primary amine end groups. When crosslinked, the macromers form hydrogels having many properties advantageous for use as medical adhesives. The medical adhesives may be preformed hydrogel adhesives or may be liquid adhesive agents that are applied as a liquid that is crosslinked in situ to form a medical adhesive.

Description

HYDROGEL MEDICAL ADHESIVES

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application Serial No. 62/506,677 filed on May 16, 2017, the disclosure of which is included herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates generally to medical adhesives and more specifically to poly(vinyl alcohol) (PVA) hydrogeis that are suitable for use as medical adhesives. The invention also relates to methods of making and using hydrogel medical adhesives.

SUMMARY OF THE INVENTION

[0003] Medical adhesives are formed from macromers having a polymeric backbone and pendant chains bearing crosslinkable groups. When crosslinked, the macromers form hydrogeis having many properties advantageous for use as medical adhesives. The medical adhesives may be preformed hydrogel adhesives or may be liquid adhesive agents that are applied as a liquid that is crosslinked in situ to form a medical adhesive,

[0004] The medical adhesives of the invention can be either degradabie or nondegradable adhesives. In one aspect, a degradabie medical adhesive can be used to protect tissue while the tissue heals, accompanied by or followed by degradation of the adhesive. The degradation profile can be tailored so that the medical adhesive degrades over hours or days or weeks.

[0005] Advantages of the present medical adhesives include good adhesion to the underlying tissue, excellent biocompatibility, ability to control and tailor the adhesiveness, and in situ adhesive formation. Some formulations may have good burst strength. Tissue adhesion of the hydrogel medical adhesives can be tailored to meet the needs of the intended application. The medical adhesives also can allow sufficient nutrient and oxygen transmission to promote wound healing and deter anaerobic bacterial growth during use.

[0006] The medical adhesives may be used for many purposes. In some cases, the medical adhesive may be an inert material used to hold together or cover tissue until it heals. In other cases, the medical adhesive may be more active and encourage hemostasis or deliver active agents to the tissue. Generally, the medical adhesives can be used for any application which currently employs a cyanoacrylate or a fibrin-based adhesive. Possible applications include, but are not limited to, surgical sealants, retinal detachment prevention, retinal hole sealant, adhesion of synthetic onlays or inlays to the comea, hemostats, teat sealants, wound protection, wound healing, dural sealants, drug or bioactive delivery devices, i.e. for antimicrobials, anti-inflammatories, stem cells.

BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Figure 1 is a chart showing the results of adhesion testing for medical adhesives according to the present disclosure,

[0008] Figure 2 illustrates swelling and degradation of medical adhesives according to the present disclosure.

[0009] Figure 3 is a bar chart showing the results of burst strength testing for medical adhesive according to the present disclosure.

DETAILED DESCRIPTION

[0010] Hydrogel medical adhesives are disclosed. As used herein the terms "medical adhesive" or "tissue adhesive" include adhesives used for any application on or in the body where adhesion to a tissue is necessary. Thus, the term includes but is not limited to sealants, hemostats, wound closures, and wound bandages. Possible applications include, but are not limited to, surgical sealants, retinal detachment prevention, retinal hole sealant, adhesion of synthetic onlays or inlays to the cornea, hemostats, teat sealants, wound protection, wound healing agent, dural sealants, drug or bioactive delivery devices, i.e. for antimicrobials, anti-inflammatories, stem cells.

[0011] Important attributes may include the medical adhesive' s tailored adhesion to the underlying tissue and optional properties such as optical clarity, color, degradability, and inertness or active agent delivery, and burst strength. In some cases, the hydrogel will be an inert material used to hold together or cover tissue until it heals. In other cases, the hydrogel will be more active and cause hemostasis or deliver active agents to the tissue.

[0012] The hydrogel medical adhesives are formed from compositions comprising macromers bearing crosslinkable side chains. The medical adhesives may be preformed or formed by crosslinking the macromers in situ on the tissue or on a device to be adhered to the tissue.

[0013] In one embodiment, the macromers include a polymeric backbone comprising units with a 1,2-diol or 1,3-diol structure (such as polyvinyl alcohol), pendant chains bearing crosslinkable groups, and modifiers that tailor the adhesive properties of the hydrogels. Crosslinking may be accomplished using photoinitiation or redox initiation. In one embodiment, the macromers are crosslinked using photoinitiation , The composition thus includes the macromers and a photoinitiator, with optionally a stabilizer and other additives. In another implementation, the macromers are crosslinked using a redox system, where the composition includes macromers, a reductant, and an oxidant.

[0014] In the in situ formed implementation, the composition may be applied to a tissue surface as a spray or stream from a syringe, pump, spray nozzle, or aerosol device. The macromers and other components are sprayed or streamed onto the tissue where the macromers crosslink in situ to form the hydrogel medical adhesive. For photoinitiation, the composition preferably contains an initiator and crosslinking is initiated by exposure to light. For redox initiation, the macromers may be delivered as a two-part composition, with one part containing the reductant and one part containing the oxidant, and crosslinking is initiated by mixing the parts.

[0015] In one embodiment, the medical adhesive delivers one or more active agents. In another embodiment, the medical adhesive is degradabie over a tailored period.

[0016] The Macromer Backbone

[0017] Poly (vinyl alcohols) which can be used as the macromer backbone include commercially available PVAs, such as, for example, Vinol® 107 from Air Products (MW=22,000 to 31,000, 98- 98,8% hydrolyzed), Poly sciences 4397 (M W=25,000, 98.5% hydrolyzed), BF 14 from Chan Chun, Elvanol® 90-50 from DuPont, and UF-120 from Unitika. Other producers are, for example, Nippon Gohsei (Gohsenol®), Monsanto (Gelvatol®), Wacker (Poly viol®), and the Japanese producers Kuraray, Deriki, and Shin-Etsu. In some cases, it is advantageous to use Mowiol® products from Hoechst, in particular those of the 3-83, 4-88, 4-98, 6-88, 6-98, 8-88, 8-98, 10-98, 20-98, 26-88, and 40-88 types.

[0018] Copolymers of hydrolyzed or partially hydrolyzed vinyl acetate may also be used. These are obtainable, for example, as hydrolyzed ethylene-vinyl acetate (EVA), or vinyl chloride-vinyl acetate, N-vinylpyrrolidone-vinyi acetate, and maleic anhydride-vinyl acetate. If the macromer backbones are, for example, copolymers of vinyl acetate and vinylpyrrolidone, it is again possible to use commercially available copolymers, for example the commercial products available under the name Luviskol® from BASF. Particular examples are Luviskol VA 37 HM, Luviskoi VA 37 E, and Luviskol VA 28. If the macromer backbones are polyvinyl acetates, Mowilith 30 from Hoechst is suitable.

[0019] The macromer backbone may preferably have a molecular weight of at least 10,000. As an upper limit, the macromer backbone may have a molecular weight of up to 1 ,000,000. Preferably, the macromer backbone has a molecular weight of up to 300,000, especially up to approximately 130,000. A desired range is from about 3 ,000 to 67,000.

[0020] PVA Macromers

[0021] The macromer can be made by general synthetic methods known to those skilled in the art. The preferred basic macromers can be made as described in U.S. Pat. Nos. 5,508,317, 5,665,840, 5,807,927, 5,849,841, 5,932,674, 5,939,489, and 6,01 1,077, the disclosures of which are included herein by reference. The macromer has at least two pendant chains containing groups that can be crosslinked. The term "group" includes single polymerizable moieties containing vinyl groups such as an acrylate or aeryfamide. The crosslinkers are desirably present in an amount of from about 0.01 to 5.0 millimole per gram of PVA (mmol/g), more desirably about 0.05 to 1.0 mmol/g. The macromer may contain more than one type of crosslinkable group. The pendant chains may be attached via hydroxy! groups of the backbone. Desirably, the pendant chains having crosslinkable groups are attached via cyclic acetal linkages to 1 ,2-diol or 1,3-diol hydroxyl groups.

[0022] Desirable crosslinkable groups include (meth)aerylamide, (meth)acrylate, styryl, vinyl ester, vinyl ketone, and vinyl ethers. Particularly desirable are ethylenically unsaturated functional groups. A particularly desirable crosslinker is N-acryloyl-aminoacetaldehyde dimethyiacetai (NAAADA) in an amount from about 0.01 to 5.0 millimole per gram of PVA (mmol/g).

[0023] Adjusting the Adhesiveness

[0024] Pendant groups may be attached to the macromer backbone to alter the adhesiveness of the formed hydrogel. These groups- adhesion promoters -as used herein include groups with primary amine end groups. Examples of useful adhesion promotors with amine groups are aminobutyraldehyde dimethyl acetal, aminoacetaldehyde dimethyl acetal, 6-amino hexanoic acid, phenylalanine, and L-tyrosine. A preferred adhesion promoter is aminobutyraldehyde dimethyl acetal attached at 0.5 to 1 ,5 mmol per gram of PVA. Medical adhesives desirably have an adhesiveness of above about 1.5N, preferably between about 1.5N and about 3.7 N. [0025] Adjusting the Swelling/ Hydrophobicity

[0026] Swelling of an adhesive is undesirable in some cases and in the present case swelling may be controlled by controlling the hydrophobicity of the hydrogel. Greater hydrophobicity means the hydrogel will absorb less water and thus will exhibit less swelling. Pendant acetate or hydroxy groups that are substituted by acetaldehyde or butyraldehyde acetals, for example, can increase the hydrophobicity of the macromers and the medical adhesive.

[0027] Applications for which it is desirable to minimize swelling include all ophthalmic applications and applications where swelling may cause the hydrogel to impinge on a nerve. Degradable hydrogel s can have increased swelling and hydrophobic pendant groups may be used to control the swelling.

[0028] In one implementation, aikane pendant groups may be attached to the PVA backbone to increase the hydrophobicity of the macromer. Examples of such groups are acetaldehyde di ethyl acetal, butyraldehyde diethyl aldehyde, and hexanal.

[0029] Crosslinking Initiators

[0030] The macromers are crosslinked using photoinitiation or redox initiation. In the case of photoinitiation, it is expedient to add an initiator that is capable of initiating free-radical crosslinking and is readily soluble in water. Examples thereof are known to the persons skilled in the art. Suitable photoinitiators include benzoins, such as benzoin; benzoin ethers, such as benzoin methyl ether, benzoin ethyl ether, benzoin isopropyl ether and benzoin phenyl ether, and benzoin acetate; acetophenones, such as acetophenone, 2,2-dimethoxyacetophenone and 1,1- dichloroacetophenone; benzyl; benzil ketal s, such as benzil dimethyl ketal and benzil diethyl ketal; anthraquinones, such as 2-methylanthraquinone, 2-ethylanthraquinone, 2-tert-butylanthraquinone, 1-chloroanthraquinone and 2-amylanthraquinone; furthermore triphenylphosphine, benzoylphosphine oxides, for example 2,4,6-trimethylbenzoyldiphenylphosphine oxide, benzophenones, such as benzophenone and 4,4'-bis(N,N'-dimethylamino)benzophenone; thioxanthones and xanthones; acridine derivatives; phenazine derivatives, quinoxaline derivatives and 1 -phenyl- 1,2-propanedi one 2-O-benzoyl oxime; 1-aminophenyl ketones and 1-hydroxyphenyi ketones, such as 1 -hydroxy cyclohexyl phenyl ketone, phenyl 1 -hydroxy! sopropyl ketone, 4- isopropyiphenyl 1 -hydroxyi sopropyl ketone, 2-hydroxy-l-[4-(2-hydroxyethoxy)phenyl]-2- methylpropan-l-one, 1 -phenyl -2-hydroxy-2-methylpropan-l -one, and 2,2-dimethoxy-l,2- diphenylethanone. [0031 ] Particularly suitable photoinitiators, which are usually used in combination with UV lamps as light source, are acetophenones, such as 2,2-dialkoxybenzophenones and hydroxyphenyl ketones, for example the initiators obtainable under the names Lucirin^iM TPO, IRGACURE^TM2959 and IRG ACURE™ 173.

[0032] For visible light polymerization, an initiator or photosensitizer and co-catalyst are used. Examples of suitable initiators are ethyl eosin, eosin, erythrosin, riboflavin, fluorescein, rose bengal, methylene blue, thionine, 5,7-diiodo-3-butoxy-6-fluorone, 2,4,6-trimethyl- benzoyldiphenylophosphine oxide and the like, examples of suitable co-catalysts are triethanolamine, arginine, methyldiethanol amine, triethylamine, or an organic peroxide (e.g., benzoyl peroxide) and the like. Another class of photoinitiators usually employed when argon ion lasers are used is benzil ketais, for example benzil dimethyl ketal,

[0033] The photoinitiators are added in effective amounts, expediently in amounts of from about 0.1 to about 2.0% by weight, in particular from 0.3 to 0.5% by weight, based on the total amount of the prepolymer. The resultant solution can be introduced onto tissues or cells or onto a base material for constructing a hydrogel adhesive device.

[0034] The macromers can alternatively be polymerized using a redox system. The reducing component includes the macromer and a reducing agent, with optionally a stabilizer and other additives. The oxidizing component includes the macromer and an oxidizing agent, with optionally a stabilizer and other additives. Both components are solutions.

[0035] The two-component formulation is applied to the tissue site by a spray or stream from a syringe, pump, spray nozzle, or aerosol device. The two components can be mixed through a static mixer and delivered onto the site. A combination of the spray and stream may be applied in a method similar to a shower head, whereby multiple streams provide the simulated broad coverage of a spray application. The macromers and other additives are sprayed or streamed onto the site whereupon they crosslink in situ to form the hydrogel-based adhesive.

[0036] Degradability

[0037] The hydrogel can be either degradabie or nondegradable. Degradability can be introduced into the hydrogel medical adhesive using crosslinkers with different numbers of aery late groups such as, for example mono-2-(acryloyloxyethyl) succinate, mono-2-(methacryloyloxyethyl) succinate, 2-carboxyethyl acrylate, and mono-2-(methacryloyloxyethyl) maleate. These can each be used in an amount from about 0.10 to 1.0 mmoi/g of PVA. The degree of degradability may be adjusted by selection of the crosslinker, and by the amount of crosslinker used. For example, 1 - ester acrylate is a slower degrading entity than 3-ester acrylate.

[0038] EXAMPLES

[0039] Example 1 : Non-Degradable PVA Hydrogel Modified with Amine Pendant Groups

[0040] Example la: Synthesis of Non-Degradable 3 IK MW Amine Modified PVA Macromer

[004 ] lOOg PVA (Mowiol® 4-88) (MW about 31,000) was introduced into a 2 liter reactor fitted with a stirrer and thermometer. IL demineralized water was added, and the mixture was heated to 95C with stirring.

[0042] After two hours, ail the PVA had dissolved to give a clear solution, which was cooled to 25C. 0.02 moles of N-acrylamidoacetaldehyde dimethyl acetal (NAAADA) and 40ml concentrated hydrochloric acid (37%) were then added. The mixture was stirred at room temperature for 20 hours. After the 20 hours, 0.12 moles aminobutyraldehyde dimethyl acetal was added and the solution was stirred at room temperature for an additional 48 hours.

[0043] Purification was carried out by ultrafiltration using a 3 kD Pelicon membrane from Miliipore. The reaction mixture was cooled to 15C and the pH was adjusted to 4.5 with 2.5N NaOH. The solution was passed through the ultrafiltration membrane and continued to a residual sodium chloride content. Before the purification was completed, the solution was adjusted to pH 7 using 0. IN NaOH.

[0044] The purification could also be carried out by precipitation. The reaction mixture can be adjusted to pH 4.5 using triethylamine and precipitated in acetone in a ratio of 1 : 10. The precipitate is separated off, dispersed three times in acetone, and vacuum dried. The resultant product has the same properties as that obtained by ultrafiltration.

[0045] Example lb: Synthesis of Non-Degradable 67K MW Amine Modified PVA Macromer

[0046] The same procedure as above in Example la was used, using lOOg PVA Mowiol® 8-88 (MW about 67,000).

[0047] Example 1 c: Synthesis of Non-Degradable 130K MW Amine Modified PVA Macromer

[0048] The same procedure as above in Example la was used, using lOOg PVA Mowiol® 18-88 (MW about 130,000).

[0049] Example 2: Slow Degradable PVA Hydrogel Modified with Pendant Amine Groups

[0050] Examples 2a-2e describe the preparation of starting PVA backbones and the crosslinker. Examples 2f- 2i describe preparation of the macromers. [0051 ] Example 2a: Synthesis of 3 IK MW Amine Modified PVA Backbone

[0052] lOOg PVA (Mowiol® 4-88) (MW about 31,000) was introduced into a 2 liter twin-jacket reactor fitted with stirrer and thermometer, 900 gram demineralized water added to give a 10% PVA solution, and the mixture heated to 9C with stirring.

[0053] After two hours, all the PVA had dissolved to give a clear solution, which was cooled to 25C. 15.89g aminobutyraidehyde dimethyl acetal in the desired amount was added, followed by the addition of 40 mL concentrated hydrochloric acid (37%). The mixture was stirred at 25C for 48 hours.

[0054] The reaction mixture was cooled, and the pH adjusted to 4.5 using triethyiamine. The amine modified PVA was then isolated out by precipitation in acetone in a ratio of 1 : 10. The precipitate was separated off, dispersed three times in acetone, and dried.

[0055] Example 2b: Synthesis of 3 IK MW Amine Modified PVA Backbone Having Increased Hydrophobicity

[0056] The amine modified PVA was prepared as described in Example 2a. After reacting the aminobutyraidehyde dimethyl acetal for 48 hours, 9.53g acetaldehyde diethylacetal (0.8 lmmol/ g PVA) was added and the mixture reacted for an additional 48 hours. The product was isolated as described in Example 2a,

[0057] Example 2c: Synthesis of 67K MW Amine Modified PVA Backbone

[0058] The same procedure as above in Example 2a was used, using l OOg PVA (Mowiol® 8-88)

(MW about 67,000).

[0059] Example 2d: Synthesis of 67k MW Amine Modified PVA Backbone Having Increased Hydrophobicity

[0060] The same procedure as above in Example 2b was used, using lOOg PVA (Mowiol® 8-88) (MW about 67,000).

[0061] Example 2e: Preparation of 3 -Ester Acrylate Cross Linker (a degradable crosslinker)\

[0062] 2.5g triethyiamine was added to a solution of 5.4g mono-2-(acryloyloxy) ethyl succinate (AOES) in 50mL dimethylformamide (DFM) and the solution was mixed for 10 min. 7.26g O- benzotriazol-l-l-N,N-N2-N2-teramethyluronium hexafluorophosphate (HBTU, 0.7 equivalent) was added and mixture stirred for lOmin. [0063] Example 2f: Preparation of Degradable 31 K. MW PVA with 3 -Ester Acrylate Cross Linkers Macromer

[0064] 30g amine modified low MW PVA (Example 2a) was dissolved in 500mL DMSO:DMF mixture (4: 1). Methoxy phenyl (5ppm) was added. The HBTU coupled AOES solution in DMF from Example 2e was added to the amine modified PVA/DMF/DMSO solution and the mixture reacted for 16 hours. Purification was carried out by precipitation in acetone in a ratio of 1 : 10. The precipitate was separated off, dispersed three times in acetone, and dried.

[0065] Example 2g: Preparation of Degradable 3 K MW Hydrophobic Modified PVA Containing 3 -Ester Acrylate Cross Linker Macromer

[0066] The same procedure as above in Example 2f was used, using 3()g PVA from Example 2b.

[0067] Example 2h: Preparation of Degradable 67K MW PVA Containing 3-Ester Acrylate Cross Linker

[0068] 30g amine modified 67k MW PVA (Example 2c) was dissolved in 500mL DMSO:DMF mixture (4: 1). Methoxy phenyl (5ppm) was added. The HBTU coupled AOES solution in DMF from Example 2e was added to the amine modified PVA/DMF/DMSO solution and the mixture reacted for 16 hours. Purification was carried out by precipitation in acetone in a ratio of 1 : 10. The precipitate was separated off, dispersed three times in acetone, and dried.

[0069] Example 2i: Preparation of Degradable 67K MW Hydrophobic Modified PVA Containing 3 -Ester Acrylate Cross Linker

[0070] The same procedure as above in Example 2h was used, using 30g PVA from Example 2d.

[0071] Example 3 : Fast Degradable PVA Hydrogel Modified with Pendant Amine Groups

[0072] Example 3a describes preparation of the cross linker and examples 3b- 3d describe preparation of the hydrogels.

[0073] Example 3a: Preparation of 1 -Ester Acrylate Cross Linker (a second degradable crosslinker)

[0074] 2.71g tri ethyl amine was added to a solution of 3 ,87g carboxyethyl acrylate (CEA) in 50 niL dimethylformamide (DFM) and the solution was mixed for 10 min. 7.83.g O-benzotriazol-1- l-N,N-N2-N2-teramethyluronium hexafluorophosphate (HBTU, 0.7 equivalent) was added and the mixture stirred for 10 min. [0075] Example 3b: Preparation of Degradable 31 MW Hydrophobic Modified PVA Containing 1 -Ester Acrylate Cross Linker

[0076] 30g amine modified high MW PVA (Example 2b) was dissolved in 500 raL DMSO:DMF mixture (4: 1). Methoxy phenyl (5ppm) was added. The HBTU coupled CEA solution in DMF from Example 3a was added to the amine modified PVA/DMF/DMSO solution and the mixture reacted for 16 hours. Purification was carried out by precipitation in acetone in a ratio of 1 : 10. The precipitate was separated off, dispersed three times in acetone, and dried.

[0077] Example 3c: Preparation of Degradable 67K MW PVA Containing 1 -Ester Acrylate Cross Linker

[0078] The same procedure as above in Example 3b was used, using 30g PVA from Example 2c.

[0079] Example 3d: Preparation of Degradable 67K MW Hydrophobic Modified PVA Containing 1 -Ester Acrylate Cross Linker

[0080] The same procedure as above in Example 3b was used, using 30g PVA from Example 2d.

[0081] Example 4: Synthesis of Control PVA Macromers (No Amine Modification)

[0082] Example 4a: Synthesis of Control 3 IK MW PVA Macromer

[0083] lOOg PVA (Mowiol® 4-88) (MW about 31,000) was introduced into a 2 liter reactor fitted with a stirrer and thermometer. 1 L demineralized water was added, and the mixture was heated to 95C with stirring.

[0084] After two hours, all the PVA had dissolved to give a clear solution, which was cooled to 25C. 0.02 moles of N-acrylamidoacetaldehyde dimethyl acetal (NAAADA) and 40ml concentrated hydrochloric acid (37%) were then added. The mixture was stirred at room temperature for 20 hours.

[0085] Purification was carried out by ultrafiltration using a 3 kD Pelicon membrane from Millipore. The reaction mixture was cooled to 25C and the pH was adjusted to 7.0 with 2.5N NaOH. The solution was passed through the ultrafiltration membrane and continued to a residual sodium chloride content.

[0086] Example 4b: Synthesis of Control 67K MW PVA Macromer

[0087] The same procedure as above in Example 4a was used, using lOOg PVA Mowiol® 8-88 (MW about 67,000). [0088] Example 4c: Synthesis of Control 130K MW PVA Macromer

[0089] The same procedure as above in Example 4a was used, using lOOg PVA Mowiol® 18-88 (MW about 130,000).

[0090] Example 5: PVA Hydrogel Preparation

[0091] PVA hydrogels were prepared by dissolving the PVA-amine acrylates of examples 1-4 in water at concentrations between 10% to 20% solids. The selected formulation was then mixed with Eosin Y-Triethanoi amine visible light photo initiator (45um / lmL of PVA solution).

[0092] Adhesion Testing

[0093] The test method used for adhesion measurements was a modified Standard Test Method for Measuring Adhesion of Organic Coatings in the Laboratory by Direct Tensile Method (ASTM D5179). This test was performed on an MTS with a 25N loadceli. A flat 6mm diameter stainless steel cylindrical probe was aligned 0.6mm above wet collagen substrate adhered to an acrylic sheet with cyanoacrylate adhesive. A volume of 0.2 ml of selected formulation with photo initiator was then injected between the probe and substrate and cured via a visible light source positioned under the acrylic sheet. The sample was subjected to the light source for a standard time of 5 minutes. Once the gel was cured the probe was lifted upward from the sample at a rate of 5 mm/min and the peak force was recorded. The peak force was the point at which the sample fails. Two possible modes of failure were observed and recorded as such.

[0094] Failure mode 1 ("adhesive"): The peak force in this context is the force at which the sample detached from the substrate. This force is considered to be the true adhesion force.

[0095] Failure mode 2 f "cohesive"): The peak force in this context is the force at which the hydrogel broke (sheared) without detaching from the substrate. In other words, the sample broke during testing leaving polymer on both the probe and the surface of the collagen, meaning that sample adhesive forces to the substrate were greater than the internal strength (cohesiveness) of the polymer matrix. If the force recorded is a cohesive failure, it is accepted that the true adhesive force is equivalent to or greater than the observed force. The recorded force of samples that failed cohesively was treated as the observed force in data analysis. [0096] The Examples and adhesion testing are summarized in Table 1. Examples 2a-2e and 3a are not included because they describe preparation of the PVA backbones or the crossiinkers.

Table 1

[0097] Degradation Study

[0098] PVA hydrogels were prepared by exposing the PVA adhesive-visible light initiator formulation to a visible light source for 5 min. 3mm x 2mm cylinders were then cut and stored in 5ml saline at 37°C and the weight change of the hydrogels was measured. The storage saline solution was exchanged every 3 days.

[0099] Burst Strength Testing

[0100] The test method used was Standard Test Method for Burst Strength of Surgical Sealants (ASTM F2392 - 04) with some modifications to accommodate testing of hydrogels. A 5cm x 5cm sheet of collagen was soaked in deionized water for 5 minutes prior to testing. A 3mm diameter hole was then punched in the sheet of collagen, and the collagen was then placed on a polypropylene surface, A volume of approximately 0.01 to 0.02 ml of selected formulation with photo initiator was injected onto the surface of the wet collagen covering the 3mm puncture. This was then placed under a light source and cured over a period of 5 minutes. Once the gel was cured, the collagen is then placed in an acrylic test rig crafted to the specification described in ASTM F2392-4 where the 3mm hole in the collagen is lined up at the center of the 15mm opening of the rig. Deionized water was then pumped into the rig at an approximate rate of 2ml/minute via a peristaltic pump and a digital pressure transducer was used to capture the pressure to the point of failure. The point of failure was defined by the decrease of pressure in the system due to leakage through the seal or the bursting of the seal. Two possible modes of failure were observed and recorded as such,

[0101] Failure mode 1 ("detachment"): The peak force in this context is the force at which the sample detached from the collagen in one cohesive piece.

[0102] Failure mode 2 ("burst"): The peak force in this context is the force at which the hydrogei burst without detaching from the collagen,

[0103] Both modes of failure are considered to be valid measurements of burst pressure.

[0104] Results

[0105] Adhesive properties

[0106] Hydrogels formed from macromers with amine modification (examples la, lb, lc, 2f, 2g, 2h, 2i, 3b, 3c, and 3d) show statistically significant increases in adhesive properties when compared to control samples formed from macromers not modified with amine (examples 4a, 4b, 4c), Examples 4a, 4b, and 4c have true adhesion of 1.042N, 1 , 135N, and 1.073N, respectively. The observed forces of the amine modified macromers all exceed the true adhesion force of 1.135N (1.502N for example la, 2.505N for example lb, and 3.208N for example lc). It is noted that failure mode 2 was the primary mode of failure observed for all the amine modified samples, whereas failure mode 1 was observed for the non-modified control samples.

[0107] There is a significant difference in the observed adhesion force between different molecular weight macromers. Examples la, lb and lc show a statistical difference in recorded adhesion between 3 I K, 67k and 130k molecular weight PVA. The hydrogei made from 3 IK PVA has an observed adhesion force of 1.502. The 67K PVA has an observed adhesion force of 2.505N, and the 130K PVA has an observed adhesion force of 3.208N, This suggests that higher molecular weight PVA improves the cohesive strength of the macromer.

[0108] There were no significant differences in observed adhesion force between degradable and non-degradable amine modified PVA hydrogels. The 1.659N observed adhesion force of example 2f (10% solids) was within the statistical margin of error of the 1.502N observed adhesion force of example la. Similarly, the 2.562N observed adhesion force of example 2h (10% solids) was within the statistical margin of error of the 2.502N observed adhesion force of example lb.

[0109] The data suggests a significant difference in observed adhesion force between hydrophobic modified and non-hydrophobic modified samples. Fast degradable samples with no hydrophobic modification (examples 2f and 2h) have a higher observed adhesion force (2.570N and 3.622N respectively) when compared to the fast degradable samples with hydrophobic modifications (example 2g and 2i; observed adhesion force of 1.993N and 2.815N respectively). This is reversed when comparing slow degradable samples (example 3c and 3d; observed adhesion force of 2.464N and 2.743 respectively). No conclusions can be drawn at this point, but it is thought that stereochemistry of the macromer may affect the cohesive properties. The faster degradable polymer crosslinker is longer than the slow degradable crosslinker and thus may allow more room for the hydrophobic modification with less interference and a more stable matrix. More research is needed.

[0110] There is a significant difference in observed adhesion force between different percent solid concentrations of the same macromer (see examples 2f (10%) and 2f (15%)). 2f (10% solids) has an observed adhesion force of 1.659N, and 2f (15% solids) has an observed adhesion force of 2.570N. This is also observed with a higher molecular weight macromer, as shown by comparing examples 2h (10% solids), with an observed adhesion force of 2.562N, and 2h (15% solids having an observed adhesion force of 3.622N.

[0111] Degradation

[01 12] The rate of swelling and degradation is affected by the number of acrylate groups on the crosslinker as shown in Figure 2. Formulations with crosslinkers with only one ester group tend to swell much less and degrade much slower than formulations with 3 -ester acrylate crosslinkers. Statistical significance was determined using a T-test p< 0.005.

[01 13] Burst Strength Properties

[01 14] The adhesion and burst pressure tests measure the adhesiveness of the hydrogel to the substrate as well as the sealant properties. The mode of failure for the burst strength is indicative of the adhesion. If no or low adhesion, the failure mode is complete detachment of the hydrogel from the collagen and if adhesion is strong the failure mode is cohesive failure. Due to the increased adhesive properties of the new hydrogel s, they also have increased sealing capability. The sealing properties can be further increased by manipulating factors of cohesion of the hydrogel through use of different molecular weights as shown by the data. The adhesive properties highlight the ability of the hydrogel to be used as an adhesive to glue two tissues together which can withstand a certain level of force before the two tissues separate, whereas the burst strength highlights the ability of the hydrogel to make a seal on a puncture or a tear which would withstand certain levels of internal pressure before the seal would be broken and causes a leak.

[0115] Hydrogels formed from macromers with amine modification (examples lb, lc, and 2i) show significant increases in burst strength compared to samples formed from macromers not modified with amine (examples 4a, 4b, and 4c). Examples 4a, 4b, and 4c have an average burst strength of 90mmHg, 51mmHg, and 58mmHg respectively. Whereas the average burst strength of the amine modified macromers lb, lc, and 2i was 182mmHg, 293mmHg, and 222mmHg respectively. The burst strength of amine modified macromer (lb and lc) is 3.5 to 3.8 times higher than the burst strength of their non-modified counterparts (4b and 4c).

[0116] Failure mode 1- detachment- was recorded as the primary mode of failure for the majority of the samples without amine modification (4a, 4b, and 4c). In the case of 4b and 4c all the samples tested resulted in the macromer detachment from the collagen in one cohesive piece at the point of failure. For sample 4a, three out of five samples exhibited mode 1 as the mode of failure,

[01 17] Failure mode 2- burst- was recorded as the mode of failure for all the amine modified samples tested (lb, lc, and 2i).

[0118] Examples 4a, 4b, and 4c show a difference in burst strength between PVA polymer molecular weights 3 IK, 67K and 130k. The macromers formed from 3 IK PVA have an average burst strength of 90mmHg. This value is significantly higher than the macromers formed from the higher 67k and 130k molecular weight PVA with an average burst strength of SlmmHg and 58mmHg respectively. This could be due to the low viscosity of the 31k MW PVA formulation which may allow it to migrate through the opening between the collagen and the plastic base. The two higher molecular weight PVA formulations have higher viscosities and are less likely to diffuse through the collagen.

[0119] The burst strength of amine modified macromer at different molecular weights also showed a difference. The 130k molecular weight PVA based macromer (lc) has a significantly higher average burst strength of 293mmHg compared to the 67k molecular weight PVA based macromer (lb) with an average burst strength of 182mmHg. [0120] There are notable differences in average burst pressure between degradable amine modified macromer with hydrophobic groups and non-degradable amine modified base PVA macromer. The 182mmHg average burst strength of example lb is less than the average burst strength of example 2i at 222mmHg. It is important to note that the margins of error for these averages do overlap. Desirably the burst pressure for the medical adhesives is between about 150mm Hg and 300 mm! fg.

Claims

The Claims

1. A medical adhesive comprising a hydrogel formed from PVA macromers modified with pendant crosslinkable groups and pendant adhesion groups having primary amine end groups, wherein the hydrogel is formed by crosslinking the crosslinkable groups.

2. The medical adhesive of claim 1 , wherein the pendant crosslinkable groups crosslink in response to UV or visible light.

3. The medical adhesive of claim I, wherein the pendant adhesion groups have primary amine end groups selected from aminobutvraldehyde dimethyl acetal, aminoacetaldehvde dimethyl acetal, 6-amino hexanoic acid, phenylalanine, and L-tyrosine.

4. The medical adhesive of claim 3, wherein the primary amine end groups are aminobutyraldehyde dimethyl acetal attached at about 0.5 to 1.5 mmol per gram of PVA.

5. The medical adhesive of claim 2 wherein the pendant crosslinkable groups are N-acryloyl- aminoacetaidehyde dimethylacetal (NAAADA) in an amount from about 0.01 to 5.0 millimole per gram of PVA (mmol/g).

6. The medical adhesive of claim 1, wherein the macromer is modified with between about 0.01 to 5.0 millimole per gram of PVA N-acrylamidoacetaldehyde dimethyl acetal (NAAADA) and between about 0.5 to 1.5 mmol per gram of PVA aminobutyraldehyde dimethyl acetal pendant adhesive promoter groups.

7. The medical adhesive of claim 1, further modified with alkane pendant groups selected from acetaidehyde diethyl acetal, butyraldehyde diethyl aldehyde, and hexanal.

8. The medical adhesive of claim 1, wherein the adhesive is used as a sealant, hemostat, wound closure, or wound bandage.

9. The medical adhesive of claim 1, wherein the adhesive is suitable for use as a surgical sealant, for retinal detachment prevention, retinal hole sealant, adhesion of synthetic onlays or inlays to the cornea, hemostat, teat sealant, wound protection, wound healing agent, durai sealant, drug or bioactive delivery device, i.e. for antimicrobials, anti-inflammatories, stem cells.

10. The medical adhesive of claim 1, wherein the adhesive can be used to repair torn retina. 1. The medical adhesive of claim 1, wherein the hydrogel is degradable.

12. The medical adhesive of claim 1 1, wherein the macromer includes pendant hydrophobic groups to control the swelling of the hydrogel as it degrades.

13. The medical adhesive of claim 1, wherein the hydrogel has an adhesion force greater than about 1 ,5 N.

14. The medical adhesive of claim 1 , wherein the hydrogel has an adhesion force greater than about 2.0 N.

15. The medical adhesive of claim 1 , wherein the hydrogel has an adhesion force between about 1.5 N and 3.7 N.

16. The medical adhesive of claim I, wherein the hydrogel is degradable and has an adhesion force greater than about 1 .5 N.

17. The medical adhesive of claim 1, wherein the hydrogel is degradable and has an adhesion force between about 1.5 N and 3.7 N.

18. The medical adhesive of claim 17, wherein the degradabiiity of the hydrogel is imparted by using a degradable crosslinker selected from mono-2~(aeryloyloxy ethyl) succinate, mono-2- (methacryloyloxy ethyl) succinate, 2-carboxy ethyl acrylate, and mono-2-(methacryloyloxy ethyl) maleate.

19. A medical adhesive comprising a hydrogel formed from PVA macromers having a molecular weight between about 31,000 and about 130,000 modified with between about 0.01 to 5.0 millimole per gram of PVA -acrylamidoacetaldehyde dimethyl acetal (NAAADA) crosslinkabie groups and between about 0.5 to 1.5 mmol per gram of PVA aminobutyraldehyde dimethyl acetal pendant adhesive promoter groups, wherein the hydrogel is formed by crosslinking the NAAADA crosslinkabie groups.

20. The medical adhesive of claim 19, wherein the adhesive is degradable.