CN1341032A - Medical adhesives - Google Patents

Abstract

Approaches have been developed to apply multicomponent medical adhesives that improve binding of the medical adhesive (106) to a substrate (104) having covalently bound adhesive components. Use of the multicomponent adhesive reduces the possibility of adverse effects due to the adhesive leaving the application site. In preferred approaches, the application of the adhesive leads to increased bond strengths. The medical adhesive (106) and/or the substrate (104) can be bioresorbable.

Description

medical adhesive

Background of the invention

The present invention relates to adhesives suitable for medical/surgical/tissue bonding, and methods of joining substrates to natural tissue or other substrates.

Surgical glues/adhesives provide optional sutures, staples, or the like to approximate the softness of the wound tissue. Certain tissues require particularly delicate suturing techniques/handling, such as nerves and particularly vital organs, where the application of surgical adhesives becomes a nearly irreparable option. In general, adhesives have the potential sealing properties and uniform pressure distribution that we need when repairing soft tissue wounds. In particular, surgical adhesives provide a means of proximate the wound without the risk of tearing the painful tissue due to the adhesive's tendency to distribute pressure throughout the length of the wound.

In general, surgical adhesives can be classified according to whether they contain synthetic polymers, natural (biological) polymers, or both. Polymers based on various synthetic urethanes have been developed into surgical glues. This urethane-based surgical adhesive composition already has relatively low toxicity, strong adhesion, and rapid treatment time. Natural surgical adhesives are usually protein-based. For example, fibrin glue contains the protein fibrinogen. Fibrinogen is commonly used in the treatment of mechanical wounds in humans or other mammals. Synthetic adhesives have the drawback of being potentially toxic. On the other hand, biological/natural adhesives generally contain relatively low binding (sticking) capabilities and fast degradation times. Previously tissue adhesives have had the adverse effect of migrating from the point of application to other sites, eg as a result of thrombosis.

Applications where medical adhesives may be used for other purposes include, for example, the production and/or implantation of medical devices.

Summary of the invention

In a first aspect, the present invention is directed to a substrate/adhesive component composition comprising a first biocompatible component having a medical adhesive covalently bonded to a biocompatible substrate layer. basal layer.

In another aspect, the invention relates to a method of securing a first biocompatible substrate to a second biocompatible substrate. The method includes contacting a second substrate layer via the substrate/adhesive component combination and the remainder of the medical adhesive to form an adhesive bond. The substrate/adhesive component composition includes a first biocompatible substrate layer having a medical adhesive component covalently bonded to the first biocompatible substrate layer.

In a further aspect, the present invention relates to an adhesive system comprising a first biocompatible base layer having a proteinaceous component of a medical adhesive, wherein the proteinaceous component forms a coating on the first biocompatible base layer. layer, and a second medical adhesive component. The coating composition is formed after more than 1 hour of contact between the protein composition and the first biocompatible substrate layer. Application of the second medical adhesive composition between the first substrate layer and the second substrate layer results in the formation of an adhesive bond after curing.

Furthermore, the present invention also relates to a method for immobilizing a first biocompatible substrate to a second biocompatible substrate. The method includes forming an adhesive bond through the combination of components of the adhesive system. The adhesive system includes a first biocompatible base layer having a protein component of a medical adhesive associated with the first biocompatible base layer, and a second medical adhesive component. Application of the second medical adhesive component between the first substrate layer and the second substrate layer results in the formation of an adhesive bond after curing such that at least a portion of the second component of the medical adhesive is between the first and second substrate layers. between the basal layers.

In another aspect, the invention relates to a method of preparing a first biocompatible substrate for bonding a second biocompatible substrate. Both a medical adhesive component and a securing compound are applied to at least a portion of the first substrate layer. The fixation compound helps maintain the connection between the first biocompatible substrate layer and the adhesive compound.

In another aspect, the invention relates to a biocompatible substrate comprising a medical adhesive component incorporated into the structural components of the substrate.

Moreover, the present invention also relates to a method of forming a biocompatible substrate by mixing a part of a component of a medical adhesive with a component of a biocompatible substrate to form a mixture, from The mixture builds a biocompatible base layer.

Additionally, the invention relates to a method of forming a prosthesis. The method includes securing the first substrate layer and the second substrate layer with a medical adhesive. The first substrate layer contains an associated adhesive component, with the remainder of the adhesive being located between the first and second substrate layers. The method further includes implanting the base layer in the patient.

Description of drawings

Figure 1. Perspective view of application of medical adhesives to attach base layer to native tissue.

Figure 2. A perspective view of a multi-component medical adhesive with one or more components partially attached to a substrate.

Figure 3. Diagram of the test setup used to measure the shear tear strength of adhesive bonds.

Figure 4. Histogram showing the average shear breaking strength measured for five different types of substrates.

Detailed description of the preferred solution

Improvements in methods of application of multi-component medical/surgical/tissue adhesives and improvements in medical devices are disclosed. In particular, one component of the medical adhesive is attached to the biocompatible substrate prior to application of the remainder of the adhesive. A substrate containing one component of the medical adhesive is secured to natural tissue or other biocompatible substrate to which the other component of the medical adhesive is applied. A base layer having one or more components of an associated medical adhesive can form part or all of the medical device, such that the medical adhesive can be used to apply the medical device to a supporting base layer, which can be Natural tissue or secondary biocompatible materials incorporated into medical devices. Although generally adhesives are very effective in joining a base layer to native tissue, the adhesive is also used to interconnect two base layers before or during implantation of the base layer in a patient. The adhesive helps reduce the number of stitches and staples, saving time in operations and complex surgical procedures. The adhesive is especially suitable for the connection of small components of medical devices that are difficult to fix with sutures or staples.

Typically, adhesives are required for repairing soft tissue wounds due to their potential sealing properties and uniform pressure distribution. The attachment of the components of the initial medical adhesive to the first substrate prior to the tissue or second substrate results in an increase in the split strength of the final adhesive bond. Furthermore, the attachment of the components of the medical adhesive to the substrate reduces the likelihood that portions of the adhesive will detach from the bond and circulate within the patient. In certain preferred embodiments, a component of the medical adhesive is covalently attached to the substrate layer. In an alternative embodiment, a component of the adhesive is incorporated into the base layer during formation of the base layer.

Referring to FIG. 1 , the overall arrangement is a structure 100 in which native tissue 102 and base layer 104 are joined by a medical adhesive 106 between base layer 104 and native tissue 102 . A portion of tissue 102 and substrate layer 104 or a portion of substrate layer 104 form a sealed or adhesive bond. Base layers other than tissue can be used in place of tissue 102, as described above. 2, the component 108 of the medical adhesive is preferably initially applied to the base layer 104, either by covalent bonding as a coating or by incorporation into the matrix of the base layer.

Adhesive tissues described herein can be used in the formation or implantation of prostheses, such as surgical patches. For example, a base layer containing an adhesive composition is used for fixation covering a wound site by placing the remainder of the adhesive either on the tissue where the base layer is to be placed, or over previously applied adhesive. The first component of the mixture, the basal layer, makes the basal layer attached to the tissue by connection and fixation. The patch may comprise multiple layers. The multiple layers may be applied continuously to the wound, or they may be partially or fully bonded prior to application to the wound. Multiple layers may be pieced together, and typically, the top layer of the prosthesis may be the same size or larger than the bottom layer. The medical adhesive can be used to hold the layers together, and/or bond the patch to the wound site. Layers can form from tissue, such as pericardial tissue, or from synthetic substances.

Alternatively, medical adhesives may be used to attach the prosthesis to the patient's natural supporting tissue. In general, portions of the prosthetic device are formed from substrate layers containing the one or more attached components of the adhesive, although all devices can be attached to one or more components of the adhesive. The remainder of the adhesive can be added to the surface of the prosthesis or natural supporting tissue comprising the first adhesive component. After the remaining components of the adhesive are applied, the prosthesis is attached to the supporting tissue. For example, a prosthesis of the heart, such as a heart valve or annulus, can be secured to natural supporting tissue in a patient (such as an annulus) with the medical adhesives described herein.

The binder is preferably present at the interface between the porous and hydrophilic first and second substrate layers. Specifically, the interface of the adhesive should be sufficiently porous so that the adhesive can be incorporated into or with the biocompatible material to obtain a gap between the substrate and the adhesive. mechanical combination. Likewise, the interface of the adhesive between the tissue and the biocompatible substrate should be sufficiently hydrophilic to allow the adhesive to wet the substrate and allow complete contact between the substrate, adhesive, and tissue. contact to form a stable bond.

Suitable composite medical adhesives include synthetic compounds, natural materials or combinations thereof. Suitable synthetic compound components of medical adhesives include, for example, urethane-based polymers. Suitable natural material components of medical adhesives include, for example, various proteinaceous materials and related adhesives. In certain embodiments, one or more components of the medical adhesive are natural materials, such as proteins, and one or more components are synthetic compounds, such as cross-linking agents.

In certain embodiments, the medical adhesive is bioresorbable, meaning that the adhesive is reabsorbed by the patient after an appropriate period of time under natural physiological conditions. The process of adhesive resorption should coincide with the natural healing process. Typically, one or more components of the medical adhesive are resorbable such that the adhesive is fully absorbed by the patient over a period of time. Thus, the natural healing process gradually provides a connection between the basal layer and native tissue through extracellular structures that can replace the adhesive. Once the adhesive is resorbed, any potential changes in the mechanical properties of the tissue introduced by the adhesive are replaced by the more natural mechanical properties of the healing native tissue.

The base layer of the medical adhesive comprising the adhesive component is prepared prior to final application of the remaining components of the medical adhesive. Determination of a suitable application time for the adhesive component of the medical adhesive on the substrate depends on the stability of the adhesive component applied to the substrate. The remainder of the medical adhesive is typically applied immediately before a seal or adhesive bond is formed between the substrate layer and the second substrate layer. In this way, an adhesive bond is formed which is maintained when the medical adhesive cures sufficiently to secure the adhesive bond.

A. Prostheses and Meshes

Prostheses attached with medical adhesives generally include a tissue or synthetic substrate as at least part of the prosthesis. The substrate layer is suitable for attachment or connection as a component of a medical adhesive. Typically, prostheses are designed to remain in the patient's body for an extended period of time. Prostheses include, for example, prosthetic hearts, prosthetic heart valves, valvuloplasty rings, blood vessels and stents, vascular grafts or tubing, gauze, suture threads, guide wires, permanently indwelling percutaneous devices , blood vessels or cardiovascular branches, skin grafts for wound healing, surgical patches, neurological growth supports, and bone replacement grafts such as joint replacement prostheses. Surgical meshes, as well as other prostheses, may be fully bioresorbable such that the entire surgical mesh is reabsorbed by the patient after a certain period of time. Biomedical devices designed to stay in the body for a certain period of time are also suitable for medical adhesives. These devices include, for example, Hickman catheters.

B, basal layer

Suitable biocompatible substrates are formed from natural materials, synthetic materials, or combinations thereof. Natural, ie, biological materials useful in the present invention include related intact living tissues, isolated cellular tissues, and regenerated cellular tissues. Such tissues can be obtained, for example, from: native heart valves, parts of native heart valves such as aortic sources, walls and leaflets, pericardial tissue, such as pericardial prostheses, tissue junctions, via grafts, tendons, ligaments, skin prostheses, blood vessels, Cartilage, dura mater, skin, bone, fascia, submucosa, umbilical cord tissue, etc.

The source of natural tissue is selected from animal species, usually mammals, such as humans, cattle, porcine, seals, horses, dogs and kangaroos. These natural tissues often include collagenous material. Native tissue is typically but not necessarily soft tissue. The tissue material is particularly suitable for the tissue formation of prostheses for heart valves. The tissue can be living tissue, isolated cellular tissue or regenerated cellular tissue. The closest description of the process of isolating cells is, for example, referred to in US Patent 5,855,620, and disclosed in PCT International Applications WO 96/32905 and WO 96/03093, both of which are incorporated herein by reference.

Tissue can be fixed by crosslinking. Fixation is by mechanical fixation, for example, by inhibiting enzymatic degradation of the tissue. Glutaraldehyde or formaldehyde are typically used for fixation, but other fixatives are also applicable, such as other difunctional aldehydes, epoxides and genipin and derivatives as described above. Tissue can be used in cross-linked or non-cross-linked form, depending on the type of tissue, use, or other factors. Typically, if a xenograft is used, the tissue is cross-linked and/or decellularized.

Relevant synthetic materials include, for example, polymers and ceramics. Ceramics include, but are not limited to, hydroxyapatite, alum, and pyrolytic carbon. If desired, ceramics can be coated with polymers, proteins or other compounds before being used as a base layer. Suitable synthetic materials include hydrogels and other synthetic materials that are not resistant to severe dehydration. Base layer materials can be prepared from synthetic polymers as well as purified biopolymers.

Suitable synthetic polymers include, but are not limited to, polyamides (such as nylon), polyesters, polystyrenes, polyacrylates, vinyl polymers (such as polyethylene, polytetrafluoroethylene, polypropylene, and polyvinyl chloride), Polycarbonate, polyurethane, polydimethylsiloxane, cellulose acetate, polymethylmethacrylate, ethylene vinyl acetate, polysulfone, nitrocellulose and similar copolymers. These synthetic polymeric materials can be woven or braided to form a matrix or base layer. Alternatively, the synthetic polymeric material may be cast or molded into suitable form.

Biopolymers can be naturally produced or prepared in vitro by fermentation and similar methods. Purified biopolymers can be formed into substrates in situ by techniques such as weaving, braiding, casting, molding, extrusion, cell alignment, and magnetic alignment. For a description of magnetic localization see, eg, R.T. Tranquillo et al., Biomaterials 17:349-357 (1996). Suitable biopolymers include, but are not limited to, collagen, elastin, silk, keratin, animal glue, polyamic acid, feline visceral suture, polysaccharides (such as cellulose and starch) and their copolymers.

The particular substrate layer used for attachment to the adhesive component may form an entire medical device or a part of a medical device. Likewise, different substrate layers can be combined to form medical devices. For example, a fixed, xenogenic tissue heart valve can be combined with a suture fabric to form a heart valve prosthesis. The fixed tissue and/or suture can be combined with one or more adhesive components. The adhesive composition may be bonded to the substrate layer either before or after the parts are bonded to the medical device. The structural order of the medical device can be influenced by the choice of the composition of the adhesive and the different methods of bonding to the substrate.

C. Medical Adhesives

Adhesives suitable for medicine/tissue/surgery preferably have composite components. Typically, adhesives are two-component, although suitable adhesives may have more than two components. In addition to the adhesive components, medical adhesives can also contain a variety of additives which will be described in detail below. As noted above, medical adhesives may comprise synthetic compounds, natural tissues/materials, or combinations thereof.

Medical adhesives are generally non-toxic. The adhesive applications described herein are proximately designed to reduce or eliminate the circulation of the adhesive and/or one or more components of the adhesive. Furthermore, by reducing or eliminating the recycling of the adhesive or adhesive components, the risk of potential migration of the adhesive is correspondingly reduced or eliminated.

With regard to synthetic adhesives, preferred adhesives include, for example, urethane-based polymers, copolymers, and mixtures of the foregoing. Polyurethanes are ester-amide derivatives of carboxylic acids. Urethane oligomers/prepolymers are formed through terminal reactive functional groups. The prepolymers are particularly suitable for forming crosslinked hybrid polymers which exhibit the range of properties desired for the polyurethane and other ingredients. For the formation of adhesives, in some embodiments, a urethane prepolymer can be used as one component of the adhesive, and one or more crosslinking agents can be used as another component of the adhesive. or multiple ingredients.

Isocyanate (-NCO)-terminated urethane prepolymers are particularly suitable as adhesive components. Polyurethanes include prepolymers of polyurethane (oligomers of urethane), which can be formed by the reaction of dichloroformic acid with diamines or diisocyanates with polyols. Polymerization methods of urethane involving diisocyanates and polyols can be used to prepare urethane prepolymers having isocyanate functional groups at their ends. Suitable urethane prepolymers can be formed by the reaction of polydiisocyanates and polyols.

Suitable polyisocyanates include, for example, aromatic polydiisocyanates having 6 to 20 carbon atoms in addition to the -NCO group, such as p-, ortho-, and m-phenylene diisocyanate (PDI), 2 , 4- and 2,6-tolylylene diisocyanate (TDI), diphenylmethane-2,4' and 4,4'-diisocyanate, diphenylmethane-2,4' and 4,4'- Diisocyanate (MDI), naphthalene-1,5-diisocyanate, triphenylmethane 4,4',4"-triisocyanate, polymethylene polyphenylene polyphenylene obtained by phosgenation of aniline-formaldehyde products Cyanates (PAPI), o- and m-isocyano-benzenesulfonyl-isocyanates, etc.; aliphatic polyisocyanates containing 2-18 carbon atoms, such as ethylene diisocyanate, tetramethylene diisocyanate , hexamethylene diisocyanate, dodecyl diisocyanate, 1,6,11-undecyl diisocyanate, 2,2,4-trimethylhexane diisocyanate, lysine diisocyanate, 2 , 6-diisocyanatomethylhexanoate, bis(2-isocyanato-ethyl)fumarate, bis(2-isocyanato-ethyl)carbonate, 2-isocyanate- Ethyl-2,6-diisocyanatohexanoate, etc.; alicyclic polyisocyanates containing 4-15 carbon atoms, such as isophorone diisocyanate, dicyclohexylmethane diisocyanate, cyclohexane diisocyanate , methylcyclohexylene diisocyanate, bis(2-isocyanato-ethyl) 4-cyclohexylene-1,2-dicarboxylate, etc.; araliphatic containing 8-15 carbon atoms Polyisocyanates, such as xylylene diisocyanate, diethylphenyl diisocyanate, etc.; and modified polyisocyanates of these polyisocyanates, containing urethane, carbodiimide, allophanate, urea, bis Urea, urethdione, urethimine, isocyanate and/or oxaolidong groups such as urethane-modified TDI, carbodiimide-modified MDI, urethane-modified MDI, etc.; mixtures of the above.

As surgical glue, this group of preferred polyisocyanates includes aromatic polyisocyanates (preferably diisocyanates), more preferably PDI, TDI (including 2,4- and 2,6-isomers, and mixtures of isomers with TDI) , MDI (including 4,4'- and 2,4'-isomers, and mixtures of isomers with MDI or PAPI), and modified polyisocyanates containing urethane, carbodiimide, allophanate Ester, urea, biuret and/or isocyanate groups, those derived from PDI, TDI and/or MDI.

Meta-PDI (hereinafter PPDI) is particularly preferred due to low toxicity. Another preferred embodiment comprises a combination of PPDI and one or more other polyisocyanates in smaller doses (usually not more than about 50% by weight, preferably not more than about 30% by weight), such as aromatic polyisocyanates, especially are TDI, MDI, modified MDI and their mixtures. Preferably, other polyisocyanates are reacted early in the prepolymer reaction to provide a PPDI terminated prepolymer.

Polyols suitable for forming prepolymers include hydrophilic polyether polyols, other polyols and mixtures of the foregoing. Typical suitable hydrophilic polyether polyols include ethylene oxide (hereinafter referred to as EO) or EO and other basic oxides (hereinafter referred to as AO) and one or more polyols containing at least two active hydrogen atoms. Adducts formed by compounds such as polyhydric alcohols, polyhydric phenols, amines, polycarboxylic acids, phosphorous acid, etc. Suitable polyhydric alcohols include dihydric alcohols such as 7-diol, propylene glycol, 1,3 and 1,4-butanediol, 1,6-hexanediol, neopentyl glycol, diethylene glycol, bis(methylol base) cyclohexane, bis(hydroxyethyl)benzene, hydrogenated bisphenol A, hydrogenated bisphenol F, polybutylene alcohol, polyester diol and silanol-terminated polysiloxane; triols such as glycerol, trihydric Methyl alcohol propane, trimethyl alcohol ethane, 1,2,3-butanetriol, 1,2,6-hexanetriol and polyestertriol; and polyhydric alcohols containing 4 to 8 or more hydroxyl groups, Such as pentaerythritol, diglycerin, d-methyl glucoside, sorbitol, xylitol, mannitol, glucose, fructose, sucrose, etc. Typical suitable polyhydric phenols include monocyclic or polycyclic phenols such as hydroquinone, catechol, resinol, 1,2,3-glucinol and bisphenols such as bisphenol F, bisphenol S, etc., and phenolic condensation products.

Amines suitable for forming polyester polyols include ammonia; alkanolamines such as mono-, di-, and tri-ethanolamines, isopropanolamine, and the like; aliphatic, aromatic, arylaliphatic, and alicyclic mono Amines, such as C ₁ -C ₂₀ alkylamines (methyl, ethyl, isopropyl, butyl, octyl and laurylamine, etc.), aniline, toluidine, naphtholamine, benzylamine, cyclohexylamine etc., aliphatic, aromatic, arylaliphatic and alicyclic polyamines, such as C ₂ -C ₆ alkyldiamines (ethylenediamine), diethylenetriamine, toluenediamine, ethylenediamine Phenyldiamine, xylylenediamine, methylenebisaniline, diphenyletherdiamine, isophoronediamine, cyclohexylenediamine, dicyclohexylmethanediamine, etc.; and heterocyclic Polyamines such as piperazine, N-aminoethyl-piperazine, and other heterocyclic polyamines are disclosed in Japanese Patent Publication No. 21044/1980.

Suitable AOs for use in combination with EO to produce polyether polyols include, for example, propylene oxide (hereinafter PO), 1,2-, 2,3-, 1,3- and 1,4-epoxybutylene alkanes, styrene oxides, epichlorohydrin, etc., and compositions as described above. AO comprising PO is preferred.

For the formation of prepolymers of urethane, the addition of EO, or a combination of EO and AO, to compounds containing active hydrogen atoms can be carried out in a conventional manner, with or without catalysts, such as basic catalysts, amine catalysts And acid catalyst, under atmospheric pressure or high pressure, single-step or multi-step reaction. The addition of EO and AO can be formed by arbitrary addition, block addition or the above-mentioned mixed methods, such as block addition after arbitrary addition. Optional addition is preferred.

Hydrophilic polyether polyols generally have an equivalent weight (molecular weight per hydroxyl group) of approximately from 100 to 5,000, preferably in the range of 200 to 3,000, wherein oxyethylene groups generally constitute at least 30%, preferably in the range of 50% by weight to 90%. An equivalent weight of the polyester polyol higher than 5,000 results in too much viscosity, and when the equivalent weight of the polyester polyol is less than 100 results in insufficient elasticity of the adhesive. The oxyethylene component of polyester polyol is as little as 30% by weight, lacks hydrophilicity, has weak binding ability with water-containing tissue, and has low curing efficiency. The proportion of primary hydroxyl groups in the preferred polyether polyol is preferably at least 30%, more preferably 50%, most preferably 70%.

Other polyols, optionally in combination with hydrophilic polyether polyols, include low molecular weight polyols and/or hydrophobic polyols. Examples of such polyols are the above-mentioned polyhydric alcohols as reactants to form hydrophilic polyether polyols, AO adducts (such as PO adducts) of these polyhydric alcohols or other compounds containing active hydrogen atoms, and Polyester polyol. Suitable polyester polyols include, for example, condensation products of dihydric or trihydric alcohols, such as ethylene glycol, propylene glycol, 1,3- and 1,4-butanediol, 1,6-hexanediol, neopentyl Alcohols, diethylene glycol, glycerol, trimethylpropanol, etc., and/or polyester polyols, such as those mentioned above, dicarboxylic acids, such as aliphatic or aromatic dicarboxylic acids, including, for example, glutaric acid, hexanoic acid Diacids, sebacic acid, fumaric acid, maleic acid, phthalic acid and terephthalic acid, or ester-forming derivatives of dicarboxylic acids, such as anhydrides and lower alkyl esters, including, for example, maleic anhydride Phthalic anhydride, dimethyl terephthalate, etc., and ring-opened lactone polymerization products including, for example, ε-caprolactone.

The preferred polyols used in the preparation of NCO-terminated urethane prepolymers have an average equivalent weight of about 100 to 5,000, more preferably 200 to 3,000 and contain 2-8 hydroxyl groups, more preferably 2- 4.

The polyisocyanate and polyol are preferably mixed in an NCO/OH ratio of about 1.5 to 5.0, preferably in the range of about 1.7 to 3.0. The final prepolymer preferably has an NCO component content of about 1% to 10% by weight and more preferably about 2% to 8% by weight. A low NCO content leads to weak cohesion and a high NCO content leads to easy bond breakage.

The reaction of polyisocyanate and polyol forms a urethane prepolymer. These prepolymers are medium molecular weight oligomers. The size of the oligomers is controlled by the relative amounts of NCO and OH functional groups. Since the NCO functional groups were added in excess, the polymerization was terminated when all the OH functional groups were completely reacted. Further polymerization of the unreacted NCO groups forms the final adhesive.

Adhesives based on bioresorbable urethane can be produced by prepolymers of suitable hydrophilic urethanes. The prepolymers of urethane are formed by organic polyisocyanates and polyester polyols derived from dicarboxylic acids with molecules of the formula,

HOOC-(A) _m -COOH

表示的电子吸引基团所表述；这里R表示包含1-8个碳原子的二价的烃基，R’表示包含1-20个碳原子的二价的烃基或卤素替代物的烃基，X是一种卤素原子或硝基或氰基，Y表示氢原子，卤素原子或硝基或氰基，n表示0，1或2。预聚物易于分解的形式导致粘合剂在几周内分解，而其它的预聚物的形式需要几个月或更长时间分解。分解时间可凭经验推算。可再吸收的氨基甲酸乙酯的粘合剂在美国专利5,173,301中Itoh等人作了进一步的讨论，题目是“外科粘合剂”，在此引入作为参考。Here, m is 0 or 1, A is -CH ₂ - or is represented by the formula -R-CO- or

Represented by the electron-attracting group; here R represents a divalent hydrocarbon group containing 1-8 carbon atoms, R' represents a divalent hydrocarbon group containing 1-20 carbon atoms or a hydrocarbon group of a halogen substitute, and X is a a halogen atom or a nitro group or a cyano group, Y represents a hydrogen atom, a halogen atom or a nitro group or a cyano group, and n represents 0, 1 or 2. The readily decomposing form of the prepolymer causes the adhesive to decompose within a few weeks, while other prepolymer forms take months or longer to decompose. The decomposition time can be estimated empirically. Resorbable urethane adhesives are further discussed by Itoh et al. in US Patent No. 5,173,301, entitled "Surgical Adhesives", incorporated herein by reference.

Suitable compositions for the second component of the urethane-based medical adhesive include polyols, such as are used to form prepolymers. The amount of polyol added is based on the number of unreacted residual functional groups in the urethane prepolymer. Alternatively, the second component of the urethane oligomer binder may be a cyano compound containing a cyano group attached to a carbon atom involved in a polymerizable double bond, such as cyanoacrylic acid and its esters. Unsaturated cyano compounds specifically include, for example, cyanoacrylic acid, cyanomethacrylic acid, methylcyanoacrylic acid, methylcyanomethacrylic acid, ethylcyanoacrylic acid, ethylcyanomethacrylic acid, isobutyl Cyanoacrylic acid, isobutylcyanomethacrylic acid, and their corresponding esters, acrylonitrile, methacrylonitrile, cyanoacrylonitrile, cyanomethacrylonitrile and mixtures thereof. Such adhesives are described in detail in US Patent 4,740,534 to Matsuda et al., incorporated herein by reference. A combination of polyols and unsaturated cyano compounds may be used as a second or additional component of the adhesive.

The urethane-based adhesive composition generally comprises 20% to 90% by weight of the urethane prepolymer, preferably 30% to 70% by weight. The ratio of urethane prepolymer to unsaturated cyano compound can be varied to obtain the desired hardness. The application of a high proportion of urethane in the adhesive results in greater elasticity. A catalyst can be added if desired.

Adhesives based on natural compositions are generally based on intrinsic natural binding affinities and corresponding biological responses. Typically, one or more components of the adhesive are a protein or protein-based compound. Protein is broadly interpreted as any compound having polypeptide components (such as amino acids), which may include derivatives of natural proteins and covalently or non-covalently bound components of polypeptides, such as other polypeptides, nucleosides, carbohydrates, and other organic or inorganic compound of. The protein component typically comprises amino acids with side chains for attachment of functional groups to the remaining binder components. Furthermore, if the base layer is a cross-linked tissue, the adhesive components react during the cross-linking reaction to replace components eliminated in the base tissue.

One type of bioadhesive is based on the protein fibrinogen. Fibrinogen, known as Factor I, is involved in the natural blood clotting process. The protein thrombin is one or two peptides from fibrinogen to fibrin. Thrombin is also involved in the clotting process of blood. Various fibrin binders are based on the crosslinking of fibrin. Fibrin glue generally involves a combination of fibrinogen, thrombin and factor XIII. Factor XIII is also involved in natural wound healing mechanisms. Factor XIII, a known fibrin-stabilizing factor, is activated by thrombin to convert soluble fibrin into insoluble thrombus. Polymerization of fibrin adhesive and covalent cross-linking of collagen to form a fluid-tight association with other tissue components. If fibrinogen, thrombin or factor XIII is associated with the substrate as a component of the adhesive, the additional protein of the adhesive can include amounts of these components. The final amount of fibrinogen, thrombin or factor XIII components in the adhesive can be adjusted, if desired, by selecting adhesive properties, such as strength and/or cure time, or a convenient procedure.

US Patent 4,818,291 to Iwatsuki et al., incorporated herein by reference, describes the conversion of silk fibroin to fibrin glue to increase its mechanical strength. Fibrin bonds can also comprise albumin, as described by Schwarz et al. in US Patent 4,414,976, incorporated herein by reference.

Other types of adhesives include adhesives of biological and synthetic composition. Typically, the biological components include proteins. For example, gelatin-resin phenolic adhesives involve gelatin-resorcinol materials that are formed by heating gelatin and resinphenols. Gelatin is formed by hydrolytic activity on the protein collagen. Formaldehyde, glutaraldehyde or the like can be used to crosslink the gelatin-resorcinol material to form an integral adhesive.

A similar binder is formed by water-soluble proteinaceous substances and di- or polymeric aldehydes. The proteinaceous material may be a purified protein or a mixture of proteins. Preferred proteins include albumin, including ovalbumin. Particularly preferred proteins include serum albumin of human or animal origin. Suitable water-soluble di- or polyaldehydes include glyoxal and glutaraldehyde. The adhesive cures within one minute or less of spray coating the acetaldehyde onto the proteinaceous material coating. Such adhesives are further described in Kowanko, US Patent 5,385,606, incorporated herein by reference.

Similar adhesives based on proteinaceous substances have been described in US Patent No. 5,583,114 to Barrows et al., incorporated herein by reference. In addition, the proteinaceous substance preferably includes serum albumin as a main component. The second component includes a difunctional crosslinker. Preferred crosslinking agents include polyethylene glycols having a molecular weight in the range of about 1,000 to 15,000. The polyethylene glycol can be modified to add leaving groups that activate crosslinkers and bind at primary or secondary amines of proteins. Suitable leaving groups include, for example, succinic acid, maleimide, phthamimdyl, other sulfimides, heterocyclic leaving groups such as imidazolyl, fragrance leaving groups such as nitrobenzene, and fluorine Alkylsulfonic acid separating groups such as tresyl (CF ₃ -CH ₂ SO ₂ -O-). The linking group can bond between the polyester polyol and the leaving group.

The adhesive may contain additives to modify the mechanical properties of the adhesive. Suitable additives include, for example, fillers, softeners and stabilizers. Typical fillers include, for example, carbon black and metal oxides, silicates, acrylic resin powders, and powders of various ceramics. Typical emollients include, for example, dibutyl phosphate, dioctyl phosphate, tricresyl phosphate, tributoxyethyl phosphate and other esters. Typical urethane-based polymer stabilizers include, for example, trimethyldihydroquinone, phenyl-β-naphthylamine, p-isopropoxydiphenylamine, diphenyl-p-anilide, and the like. Protein-based binders may also contain sugars such as sugar gum, dextrose or sucrose to enhance solubility, and stabilizers, including heparin. The fibrin glue may also contain other components such as fibrinolytic inhibitors (anti-fibrinolytic agents), eg, aprotinin and/or transexamic acid, and calcium chloride.

D. Bonding of Adhesive Components to Substrate

The adhesive of one or more components is generally attached to at least a portion of the substrate. Although the joined components may comprise more than one component, the joined components lack at least one essential component during the formation of the adhesive. In other words, it cannot form a complete adhesive by itself through the connection of one or some components, and when it is added with other components, it forms a strong adhesive bond. The adhesive component attached to the substrate layer can be coated, covalently bonded to the substrate layer, and/or mixed into the matrix or structure of the substrate.

Additional proteins of the adhesive include all adhesive components and additives not originally attached to the substrate. The additional portion of the adhesive may include additional amounts of the connecting adhesive component. Additional moieties of the adhesive may be added to the natural tissue surface or to a second substrate to be attached to the substrate, for example as a coating or covalently bonded, or applied to a substrate to which the adhesive component is attached. bottom part.

Once all parts of the adhesive are applied, the base layer glue is bonded to the native tissue so that the base layer adheres to the native tissue. The adhesive bond has an adhesive strength at least three times higher than an adhesive having one or more adhesive components linking the tissue without the additional portion. Although the base layer is usually bonded to native tissue, the base layer may be bonded to a second base layer before or during the implantation process of the medical device. Thus, the composite substrate layers of medical adhesive bonded to each other are preferably implanted into the patient before, during or after the adhesive has fully cured. The mutual contact between substrates using the process herein has advantages related to adhesive positioning and generally increases bond strength.

The component or components to be attached to the substrate layer can be selected by the adhesive ability of the adhesive and the adhesive bond of the remainder of the adhesive. In certain aspects, any number of suitable ingredients in the adhesive can be bonded to the substrate layer. For urethane adhesives, the urethane polymer coating can be bonded to the substrate layer. For protein-based adhesives, proteins can often bind to the substrate. If desired, a portion of the adhesive may comprise the linking component of one adhesive component, while the other portion of the substrate layer has the linking component of another adhesive. The two parts of the different adhesive compositions can be partially or fully covered if desired.

Typically, the adhesive component is attached to the base layer in such a large quantity that the base layer does not readily separate for the time required for the adhesive to cure. For some adhesive compositions, application of the adhesive composition as a coating directly to the selected substrate layer is sufficient to provide effective bond strength. The adhesive strength of the adhesive component layer is dependent on the natural bond between the substrate material and the adhesive component, the effect of natural wetting of the adhesive component surface, the solubility of the adhesive component in water and/or the influence of other similar effects.

The attached adhesive composition and substrate layer can be attached by covalent bonding or by application of a coating. Preferably, the composition coating is stable over a period of time, more preferably several days or longer under appropriate storage. Coatings are formed after at least one hour, and sometimes two hours or more are required, of the bonding component and the substrate, eg, the bonding component is fully attached to the substrate by various non-covalent linkages. As will be further described below, the adhesive composition and the adhesive coat of the base layer are prepared and stored prior to use. In order to join the adhesive composition and the substrate layer, the substrate may be placed in a solution containing the adhesive composition. Alternatively, the adhesive composition may be brushed onto the surface, or applied or sprayed with a sprayer or the like. In an alternative embodiment, the attached adhesive component may be incorporated into the base layer matrix.

In order to form a coating containing a medical adhesive component, the method allows selection of an appropriate base material and adhesive component. For example, if the adhesive composition and base layer are not sensitive to drying, the adhesive composition can be added to the base layer and dried to remove the solvent. Alternatively, the adhesive component may be applied as a concentrated solvent, keeping the final composition moist to prevent the substrate/adhesive component composition from drying out. Containers for storing moisture sensitive agents of substrate/adhesive component compositions are described in US PCT/US98/03519 entitled "Reservoirs", incorporated herein by reference.

In certain preferred embodiments, a component of the medical adhesive is covalently bonded to the substrate. If the covalently bonded adhesive components are proteins, there are a number of methods of covalent bonding that can be attached, depending on the nature of the substrate. For tissue-based substrates, standard tissue crosslinkers can be used for covalent linkage, such as bifunctional aldehydes, including glutaraldehyde. The cross-linking agent binds to the proteins of the adhesive component and to the proteins of the tissue basal layer.

For synthetic substrates and proteinaceous or non-proteinaceous adhesive components, suitable crosslinkers can be used for covalent attachment. The molecules of the crosslinking agent may have one or more functional groups active for the adhesion of the adhesive or one or more functional groups active for the adhesion of the substrate layer. Suitable base layers have functional groups that can be chemically crosslinked. Depending on the nature of the synthetic substrate material, appropriate functional groups for the crosslinker can be selected. The functional group of the crosslinking agent is a functional group that can be identified as being capable of chemically crosslinking with the synthetic polymer.

For example, chlorosulfonated polyethylene as a base material can be reacted with crosslinking compounds containing alcohol or amine functionality. In this way, compounds containing aldehyde and alcohol or amine functional groups can be cross-linked between the protein binding component and the chlorosulfonated polyethylene substrate. Similarly, polystyrene substrates can be reacted with halogenated hydrocarbons. Therefore, suitable crosslinkers that can enable binding of proteins to polystyrene substrates have both aldehyde and halomethyl functionality.

If the binding component is covalently attached to the substrate, the binding conditions can be adjusted to covalently bind the desired amount of the binding component without inactivating the binding ability of the component. To this end, the concentration of the adhesive and the adhesive components can be adjusted. The protein binding component typically has a concentration in the binding solution of about from 1 ng protein/ml to 50 μg/ml, preferably 25 ng protein/ml to 100 μg/ml. A suitable concentration can be selected empirically.

For attachment of the protein adhesive component to the tissue substrate, bonding with a cross-linking agent can be performed under carefully controlled conditions so as not to inactivate the adhesive properties of the bonding component. In particular, crosslinking is preferably carried out in a dilute solution of a crosslinking agent, such as glutaraldehyde. Crosslinking is preferably performed at a crosslinking agent concentration of less than 0.1%, more preferably less than 0.05%, even more preferably 0.005% to 0.02%. Percentage values are obtained by diluting by volume a concentrated volume percent glutaraldehyde stock solution, which is usually a 50% by volume stock solution, according to conventional amounts used in the art.

Cross-linking of the proteinaceous adhesive component to the tissue substrate requires at least 5 minutes, usually from about 15 minutes to 24 hours or more. For glutaraldehyde crosslinking of certain proteins and tissue basal layers, the extent of adhesion was observed to be relatively rapid relative to crosslinking time, see co-applied assigned US Patent entitled "Prosthesis with Attached Growth Factors" 09/186,810, incorporated herein by reference. The preferred crosslinking time can be selected empirically based on the disclosure herein. Under the preferred moderate conditions described herein, the tissue basal layer generally cannot be appreciably immobilized by the cross-linking agent.

For tissue-based substrates, the solution containing the adhesive component is preferably buffered at near physiological pH, ranging from about 6.0 to 8.5, more preferably from about 6.9 to 7.5. Suitable buffers may be based, for example, on compounds such as phosphates, borates, bicarbonates, carbonates, cacodylates, citrates, and other organic buffers such as tris(hydroxymethyl)methylamine (TRIS), N-(2-hydroxyethylamine)piperazine-N'-(2-ethanesulfonic acid) (HEPES), and morpholinopropanesulfonic acid (MOPS).

In an alternative embodiment, photochemical coupling can be used to induce covalent coupling of the adhesive component and the substrate layer. Photochemical coupling is based on the application of high-energy light, for example, ultraviolet light, to form reaction intermediates of certain functional groups. These intermediates can form carbon-carbon bonds between the two compositions. Aryl ketone functions are particularly useful therein. When performing photochemical coupling, a crosslinker is not necessary for covalent bonding between the adhesive component and the substrate.

Photochemical coupling can be used to link protein binding components to tissue substrates. For example, Dunkirk et al. J. Biomaterials Applications 6:131-156 (1991 ), incorporated herein by reference. Since photochemical coupling usually also crosslinks tissue, the tissue may or may not be separately crosslinked, ie photofixed. Alternatively, photochemical coupling may be used to attach the linker to the tissue before, after or during attachment of the linker to the proteinaceous adhesive component.

UV light can be used to crosslink various synthetic polymers and substrates. In particular, ethylene polymers undergo crosslinking when exposed to radiation due to a free radical mechanism. Cross-linking agents can be used with those known to be photoactive. In addition, various polymer side chain groups can be used for photoreaction including, for example, alkyne, anthracene, benzothiophene dioxide, chalcone, cinnamate, lavenderin, dibenzazepine, diphenylcyclopropene carboxylate , episulfide, maleimide, styrylpyridine, stilbene, 1,2,3-thiadiazole, and thymine. Accordingly, the base polymer and/or the adhesive component may include these photoactivatable groups.

In an alternative preferred embodiment, the medical adhesive component may be incorporated into the structure/matrix of the biocompatible substrate when the substrate layer is formed. In particular, at an appropriate time in the preparation of the substrate, an amount of the medical adhesive composition can be mixed with the composition of the substrate layer to form a mixture. When the base layer is formed, the base layer is included in the molecular structure of the medical adhesive composition. Thus, part or all of the final substrate comprises the medical adhesive composition distributed through the substrate matrix. The biocompatible base layer may comprise parts and/or layers such that the medical adhesive composition is distributed only within the parts and/or layers forming the biocompatible base layer.

The polymeric base layer can be formed by conventional polymerization processes. The polymer can be a synthetic polymer or a natural polymer, such as purified collagen. The base material can be chosen so that the components of the surgical glue are not broken down during processing. For example, if the adhesive component is heat sensitive, the substrate layer processing method can be selected so that the adhesive component does not need to be added to the hot substrate material. In this case, a solvent forming method or the like may be used instead of the thermoforming method. Concentrations of the adhesive components can be selected empirically to provide sufficient adhesion to complete an adhesive bond with natural tissue or other substrates after addition of the remaining components of the adhesive.

E. Adhesive bond formation

The rest of the binder can be added in various ways. For example, the additional portion of the adhesive may be applied directly to a portion of natural tissue or a second substrate layer to which the first substrate layer is applied. The second substrate layer may or may not include an attached adhesive component. Alternatively, the adhesive may be applied to the substrate layer with the attached adhesive component prior to contacting the substrate layer with native tissue or a second substrate layer. The remainder of the medical adhesive can be brushed on its surface, applied from the device, or by dipping the appropriate substrate layer into a solution containing other ingredients, or sprayed as an aqueous sol, etc. The consistency of another portion of the medical adhesive may indicate its particular suitability for application.

The additional portion of the adhesive typically includes one or more additional adhesive components other than the adhesive component attached to the substrate layer. Additional portions of the adhesive may include additional amounts of one or more adhesive components attached to the substrate layer. Additional portions of the adhesive may include additives.

If the additional portion of the adhesive is applied to the natural tissue or the second substrate prior to the formation of the adhesive bond, the formation of the adhesive bond involves the combination of different components of the adhesive. If a further portion of the adhesive is applied to the bonding component of the adhesive base layer, its final structure can be distinguished from the adhesive coating. Thus, either way of application of the additional portion of the adhesive, the substrate layer and the final structure of the adhesive are distinguished from a fully mixed additive coating of the adhesive, including mixing all components of the adhesive.

Typically, the additional portion of adhesive is added just before the interface is formed, although the exact timing can be adjusted according to various factors. Time-related factors include the rate of fixation, the length of the surgical procedure, and the stability of the isolated components under environmental conditions, such as applied humidity. Preferred adhesive cure times range from about 1 minute to 5 hours, more preferably from about 5 minutes to 1 hour, most preferably from about 5 minutes to 30 minutes. After the additional portion of the medical adhesive is applied, the base layer is brought into contact with native tissue or a second base layer at the desired attachment point. The adhesive is fully cured when the adhesive bond can withstand the standard pressure applied to the adhesive bond without additional support. Standard pressure can cover many valid ranges. For example, the pressure is relatively low for adhesive support of a surgical mesh or relatively high for adhesive support of a heart valve annulus prosthesis. When fully cured, the adhesive achieves a level of adhesive strength that is as durable as desired.

For the initial curing of the adhesive, the caregiver can hold the base layer in place for an extended period of time to achieve full cure. Alternatively, screw pliers or paper clips or the like can be used to hold the base layer in place. These allow the application of adhesives with fast cure rates. Alternatively, or in addition, some sutures or staples may be used to hold the base layer in place. Sutures and staples are usually used less frequently than medical adhesives. The limited use of sutures and/or staples is to provide stabilization of the adhesive bond early in cure and prevent the failure of the adhesive bond bond.

Properties of Adhesive Bonds

Formation of a connection, seal or bond between the base layer and natural tissue or other base layer comprising at least a portion of the surgical glue after application of the additional portion of the adhesive bonded. The presence of adhesive bonds does not indicate any connection characteristics regarding the junction between the native tissue/second basal layer and the first basal layer. The connection may involve a "wireless suture connection" between the native tissue/second basal layer and the first basal layer, resulting in a smooth connection between the two substances.

The adhesive includes a covered area of adhesive between the first substrate layer and the tissue or other substrate layer. The adhesive bond preferably has a bond strength of at least 75 g/cm ² , more preferably at least 100 g/cm ² . Since it is not possible to measure the strength of the actual adhesive bond in the patient, the strength of the bond is referenced to the strength between the equivalent of the basal layer and the equivalent of the actual adhesive bond of native tissue. Referring to FIG. 3 , the bond strength is measured by forming a bond between the adhesive bond 150 and the nascent tissue 154 of the covering edge of the basal layer portion 152, i.e., non-degraded tissue without fixation, so that the basal layer 152 and the tissue 154 are bonded together. Reverse stretching of the bond 150. If appropriate, a different basal layer can be used to replace the tissue, as appropriate. The stretched edges from the adhesive keys are secured between clips 160,162,164,166.

The adhesive substrate layers 152, 154, located between the clips 160, 162, 164, 166, are stretched, see Fig. 3, in all directions from the adhesive bond 150 until the adhesive bond breaks under shear. The shear force (breaking strength) value at which the adhesive bond breaks is the determined adhesive bond strength. Although the actual adhesive bond is not two-dimensional, ie, planar, the bond strength is evaluated by the consistency of the two-dimensional adhesive bond. If a good hemostat or liquid seal is formed around the adhesive bond, the bond strength of the non-two-dimensional adhesive bond is usually roughly equivalent to the area of the adhesive bond multiplied by the two-dimensional bond strength per unit area.

For biocompatible adhesive bonds, the preferred time period for the adhesive bond to be resorbed is when the basal layer and tissue are brought together during the natural healing process. In this way, the adhesive is replaced by natural tissue, which does not contain intact adhesive bonds. The various resorption rates can be adjusted empirically to keep the adhesive at least long enough that the bond strength of the bond is not broken. The length of wound healing time can depend on the size of the wound and the pressure on the wound tissue. For example, tissue with little stress may heal after a few days, while tissue with some stress may take a relatively long time.

G. Biologically active additives

The adhesive may contain a biological response altering agent. Inclusion of the biological response modifying agent in the adhesive may result in gradual release of the biological response modifying agent, especially if the adhesive is bioresorbable. Suitable biological response modifying agents include, for example, antibacterial agents, anticalcific agents and growth factors. Typically, the supplement is applied topically in combination with the rest of the supplement, although the protein supplement may also adhere to the substrate if the method of adhesion is also bonding of the protein supplement to the substrate.

Antibacterial agents include, for example, organic chemical agent antibiotics and metal ion-containing antibacterial agents. Organic antibiotics include, for example, penicillin and the like. Antibacterial agents containing metal ions include, for example, Ag, Au, Pt, Pd, Ir, Cu, Sn, Sb, Pb, Bi, Zn ions and combinations thereof. For the bonding of metal ion-containing antimicrobial agent and prosthesis, the prosthesis or a part of the prosthesis can be soaked in a liquid containing metal ion antibacterial agent, such as silver nitrate solution. Alternatively, the solution may be applied to the substrate by spraying, brushing or the like.

Alternatively, the metal ion-containing antimicrobial agent may be in the form of a low solubility metal ion-containing antimicrobial agent salt solution. Silver-containing compounds are particularly preferred. Suitable silver compounds include, for example, silver chloride, silver bromide, silver iodide, silver carbonate and silver phosphate. Suitable copper compounds include, for example, copper stearate and copper phosphate. Suitable zinc compounds include, for example, zinc stearate and zinc phosphate. Similarly, suitable palladium compounds include, for example, palladium acetate.

The use of metal ion-containing antibiotics to further reduce the risk of infection is described in US Patent No. 08/974,992 entitled "Adhesion of Medical Products and Metal Antibiotics", which is incorporated herein by reference. Antibiotics containing metal ions can be delivered using exogenous storage structures as described in US Patent No. 08/787,139 to Tweden et al., entitled "Silver-Containing Delivery Systems," incorporated herein by reference.

Certain polyvalent metal ions are effective in reducing calcification of prostheses. Preferred anti-calcification ions include, for example, aluminum ions (Al ⁺³ ) and iron ions (Fe ⁺³ ). Other suitable metal ions include, for example, manganese, zinc, gallium, lanthanum and beryllium ions. In order to introduce polyvalent anticalcific metal ions into the prosthesis, the prosthesis or a part of the prosthesis can be impregnated with a fluid containing anticalcific ions. For example, aluminum nitrate or ferric nitrate can be used. Alternatively, the anticalcification ions are deposited as relatively insoluble salts in contact with the prosthesis or part of the prosthesis by adding selected anions to a soluble salt solution of the anticalcification ions. For example, aluminum palmitate can be precipitated from an aqueous solution of aluminum chloride by adding palmitic acid, and iron phosphate can be precipitated from a solution of ferric chloride.

Additionally, it has been shown that exogenous storage structures can be used to deliver multivalent cations. See US Patent 08/690,661 to Schroeder et al., entitled "Calcification-Inhibiting Biological Substances," incorporated herein by reference. Exogenous storage structures with stored anticalcific ions can be combined with antimicrobial metal element-containing deposits.

A biological response modifier can be a growth factor. Particularly preferred growth factors include, for example, vascular endothelial growth factor (VEGF). VEGF promotes the proliferation of endothelial cells of vascular tissue. VEGF is a protein that may be contained within an adhesive component that is associated with the base layer or with another component of the bond. The incorporation of VSG into prostheses is further described in US Patent Nos. 09/014,087 and 09/186,810 to Carlyle et al., entitled "Prostheses with Associated Growth Factors," both of which are incorporated herein by reference.

H. Storage, Packaging, Distribution and Application

The adhesive composition is bonded to the base layer and the improved base layer can be stored. Storage that minimizes microbial contamination is preferred. For example, the modified moisture-insensitive substrate layer can be stored in a dry, airtight container. Alternatively, the modified substrate can be stored with the preservative solution in a sterile, sealed container. The properties of the preservative solution should be compatible with the substrate and maintain the activity of the adhesive components. For example, a crosslinked tissue basal layer containing a protein binding component can be stored in dilute aqueous glutaraldehyde solution. It should be anticipated that the loss of the bonded adhesive components over time, or that the efficiency of the bonded adhesive components may decrease. Additives including antioxidants, such as ascorbic acid, may be added to the storage solution to reduce the loss of efficiency of the binding ingredients during storage.

For distribution, the modified substrate can be placed in sealed and sterile containers. Containers are usually marked with a date that reflects the maximum recommended storage time taking into account possible degradation of the adhesive components and other factors. The container package includes instructions for proper use of the substrate and labeling as appropriate and/or required. The container is distributed to healthcare workers for appropriate medical procedures. . If the medical substance is stored in a liquid, the healthcare worker cleans the substrate after removing it from the storage container before use. The remaining ingredients may or may not be dispensed with the modified base layer. If the remaining components do not dispense with the modified substrate, in some cases the remaining components may be purchased separately as a separate adhesive product.

Optionally, the base layer may be modified during transfer from the product to a hospital or other remote location. In certain instances, the modified substrate can only be stored for a short period of time before use. In some cases, the base layer and the adhesive composition require modification of the base layer applied separately or together. Suitable instructions may be dispensed with the base layer, one or more adhesive components/parts, or combinations thereof. For short-term storage, the modified substrate can be kept in the solution used to modify the substrate. Alternatively, the modified base layer can be applied immediately after the base layer modification is complete.

Example

This example is intended to demonstrate the increased bond strength resulting from the covalent attachment of components of a fibrous adhesive to a tissue binding component.

Samples were obtained from the wall of a porcine aorta. Two segments of aorta approximately 2 cm x 6 cm were cut from the same vessel from the valve. Before cutting the sample, the length dimension of each vessel segment corresponds to the cardinal direction of the vessel. Twelve aortic segments (six pairs) were cross-linked and stored in 0.9% saline (Saline, Baxter Health Care Corp., Deerfield, IL) containing 0.5 percent glutaraldehyde for approximately 3 weeks. The glutaraldehyde solution was prepared by diluting the glutaraldehyde stock solution 50% by volume per liter.

Eighteen non-crosslinked aorta segments (nine pairs from nine sections of the aorta) were prepared. Six fragments (three pairs) were placed in 50 ml of 0.9% saline overnight. Another six aortic segments (three pairs) were placed overnight in saline containing fibrin and the other six aortic segments (three pairs) were placed overnight in saline containing fibrinogen (80% active, ie clotted). A concentrated fibrin solution was obtained by dissolving 5.0 g of fibrin (obtained from bovine blood, Sigma Chemical Company, lot 110H9304) in 100 ml of 0.9% salt. Similarly, a fibrinogen solution was formed by dissolving 5.0 g of fibrinogen (Sigma Chemical, lot 64H9300) in 100 ml of 0.9% salt. Then, aorta segments stored overnight in fibrin or fibrinogen solution were placed in phosphate buffer with 0.5% glutaraldehyde for two hours, respectively. After two hours in glutaraldehyde salt solution, samples were removed and incubated in 0.1 M tris buffer (highly purified tris, tris(hydroxymethyl)aminomethane, Gibco BRL, LifeTechnologies, Inc., Grand Island, NY) 1 hour.

Corresponding cross-linked or non-cross-linked segments originating from the same vessel are held together by adhesive-containing glue. Approximately 2 square centimeters of adhesive was applied to the surface of the end of one tissue segment. The adhesive was a fibrin glue (CryoSeal ^™ from Thermo Genesis Corp, Rancho Cordova, CA, prepared using 5,000 units/5 ml of fibrin from Park Davis, Moms Plains, NJ), except for three pairs of cross-linked aortic segments (marked CY/x-linked) to cyanoacrylate glue Duro ^(R) (Super Glue, Hartford, CT). The fibrin viscose sample is labeled FG, the cross-linked tissue treated as "x-linked", untreated as "fresh", fibrinogen-treated as "fibrinogen", fibrin-treated Expressed as "fibrin". Fibrin glue is applied through two spouts, which combine the multiple components through a single tube prior to use. The samples were covered and the adhesive was allowed to cure for approximately 20 minutes.

The strength of the bond was tested on an Instron 501b Load Cell, Model Sintech 1/s from the Sintech Division of MTS Systems Corporation (Research Triangle Park, NC). Two connective tissue segments are held in place on the load cell, applying force to the adhesive bond. The load capable of producing sufficient shear to separate the adhesive bonds was measured on the structure, as shown generally in FIG. 3 .

The results are listed in Table 1 and the mean values are shown in Figure 4.

Table 1 sample serial number Strength (1bs) Strength (g) g/ ^cm2 CY/x-linked 1 4.40 969.76 484.88 2 5.70 1256.28 628.14 3 7.40 1630.96 815.48 average value 5.83 1285.67 642.83 Std. Dev. 1.50 331.58 165.79 FG/x-linked 1 0.40 88.16 44.08 2 0.30 66.12 33.06 3 0.20 44.08 22.04 average value 0.30 66.12 33.06 Std. Dev. 0.10 22.04 11.02 FG/fresh 1 0.40 88.16 44.08 2 0.60 132.24 66.12 3 0.50 110.20 55.10 average value 0.50 110.20 55.10 Std. Dev. 0.10 22.04 11.02 FG/fibrinogen 1 1.40 308.56 154.28 2 2.20 484.88 242.44 3 2.30 506.92 253.46 average value 1.97 433.45 216.73 Std. Dev. 0.49 108.72 54.36 FG/fibrin 1 1.00 220.40 110.20 2 0.50 110.20 55.10 3 0.80 176.32 88.16 average value 0.77 168.97 84.49 Std. Dev. 0.25 55.47 27.73

Synthetic cyanoacrylate has the strongest bond. Application of cross-linked fibrinogen to the fragments prior to fibrin glue application resulted in an almost 4-fold increase in tear strength. Covalent attachment of fibrin resulted in an increase, but the magnitude of the increase was not statistically significant. Thus, covalent bonding of adhesive components can lead to a significant increase in bond strength.

The embodiments described above illustrate the present invention but do not limit the present invention. Further implementation embodiments are in the following claims. Although the present invention has been described with reference to preferred embodiments, changes in form and detail can be made by workers skilled in the art without departing from the spirit and scope of the invention.

Claims (31)

1. A substrate/adhesive component composition comprising a first substrate having a component of a medical adhesive covalently bonded to the substrate. 2. The composition of claim 1, wherein the binder component comprises a protein. 3. The composition of claim 2, wherein the protein comprises fibrinogen. 4. The composition of claim 2, wherein the protein comprises albumin. 5. The composition of claim 1, wherein the medical adhesive component comprises a prepolymer of urethane. 6. The composition of claim 1, wherein the first substrate layer comprises tissue. 7. The composition of claim 6, wherein the tissue comprises a cross-linked tissue. 8. The composition of claim 1, wherein the first substrate layer comprises a synthetic matrix. 9. A method of securing a first substrate to a second substrate comprising contacting the composition of claim 1 and the remainder of the medical adhesive with the second substrate to form an adhesive bond. 10. The method of claim 9, wherein the second substrate layer comprises tissue. 11. The method of claim 8, wherein the first base layer comprises a plurality of layers. 12. An adhesive system comprising a first base layer of a proteinaceous composition with a medical adhesive, wherein the proteinaceous composition forms a coating on the first basement layer after the proteinaceous composition has been in contact with the first basement for more than 1 hour layer, and a second medical adhesive composition, wherein application of the second surgical glue composition between the first substrate layer and the second substrate layer results in the formation of an adhesive bond after curing. 13. The adhesive system of claim 12, wherein the medical adhesive comprises a resorbable composition. 14. The adhesive system of claim 12, wherein the first surgical glue component is covalently bonded to the first substrate layer. 15. The adhesive system of claim 12, wherein at least a portion of the first substrate layer has a coating comprising a resorbable polymer having a first surgical glue added thereto components to connect the first surgical glue component to the base layer. 16. The adhesive system of claim 12, wherein said first substrate layer comprises a cross-linked texture. 17. The adhesive system of claim 12, wherein said first base layer comprises a synthetic matrix. 18. The adhesive system of claim 12, wherein the second substrate layer comprises natural tissue. 19. A method of securing a first substrate to a second substrate, the method comprising combining components of the system of claim 11 to form an adhesive bond such that at least a portion of the second component of the surgical glue between the first and second substrate layers. 20. The method of claim 19, wherein the first substrate layer of the coating having an adhesive composition is stored in a sealed, sterile container prior to forming the adhesive bond. 21. A method of preparing a first substrate layer for bonding to a second substrate layer, the method comprising applying a medical adhesive composition and a fixing compound to at least a portion of the first substrate layer. 22. The method of claim 21, wherein the immobilizing compound is a crosslinking reagent. 23. The method of claim 21 , wherein the immobilizing compound causes covalent bonding of components of the surgical glue to the first substrate layer. 24. The method of claim 21, wherein the immobilizing compound is a resorbable polymer. 25. A base layer comprising a medical adhesive component added to the matrix component of the base layer. 26. The base layer of claim 25, wherein the matrix component of the base layer comprises a synthetic compound. 27. The base layer of claim 25, wherein the matrix component of the base layer comprises a natural polymer. 28. A method of forming a substrate comprising constructing the substrate from the mixture by mixing a portion of a component of a medical adhesive with a component of the substrate to form a mixture. 29. A method of forming a prosthesis, the method comprising: securing a first substrate and a second substrate with a medical adhesive, wherein the first substrate contains an associated adhesive component, wherein the remainder of the adhesive is located between the first and second substrates . 30. The method of claim 29 further comprising implanting the base layer in the patient, wherein said implanting occurs before the adhesive is fully cured. 31. The method of claim 29 further comprising implanting the base layer in the patient, wherein said implanting occurs after the adhesive has fully cured.

Images