WO2000043050A1 - Medical adhesives - Google Patents
Medical adhesives Download PDFInfo
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- WO2000043050A1 WO2000043050A1 PCT/US2000/001215 US0001215W WO0043050A1 WO 2000043050 A1 WO2000043050 A1 WO 2000043050A1 US 0001215 W US0001215 W US 0001215W WO 0043050 A1 WO0043050 A1 WO 0043050A1
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- WIPO (PCT)
- Prior art keywords
- substrate
- adhesive
- component
- tissue
- medical
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/10—Polypeptides; Proteins
- A61L24/108—Specific proteins or polypeptides not covered by groups A61L24/102 - A61L24/106
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0042—Materials resorbable by the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/0047—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/043—Mixtures of macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/10—Polypeptides; Proteins
- A61L24/106—Fibrin; Fibrinogen
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L75/00—Compositions of polyureas or polyurethanes; Compositions of derivatives of such polymers
- C08L75/04—Polyurethanes
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L89/00—Compositions of proteins; Compositions of derivatives thereof
- C08L89/04—Products derived from waste materials, e.g. horn, hoof or hair
- C08L89/06—Products derived from waste materials, e.g. horn, hoof or hair derived from leather or skin, e.g. gelatin
Definitions
- the invention relates to adhesives suitable for use as medical/surgical/tissue adhesives and associated methods for attaching substrates to native tissue or other substrates.
- Surgical glues/adhesives provide an alternative to sutures, staples and the like for closing wounds in soft tissue.
- Certain tissues, such as nerves and particular vital organs, are too delicate for suturing or stapling, so the use of surgical adhesives may be one of few viable repair options.
- the use of an adhesive to repair wounds in soft tissue is desirable due to its potential sealing properties and uniform stress distribution.
- surgical adhesives provide a means for closing a wound without introducing a risk of tearing tissue since adhesives tend to distribute the stress over the length of the wound .
- surgical adhesives can be classified according to whether they include synthetic polymers, natural (biological) polymers or both. A variety of synthetic urethane based polymers have been developed as surgical glues.
- the urethane based surgical adhesive compounds have been developed based on relatively low toxicity, strong binding and fast cure times.
- Natural surgical adhesives generally are based on proteins.
- fibrin glues include the protein fibrinogen. Fibrinogen is used in natural wound healing mechanisms in humans and other mammals.
- Synthetic adhesives have the disadvantage of being potentially toxic.
- biological/ natural adhesives generally have relatively low binding (cohesive) strengths and rapid degradation times. Previous tissue adhesives have migrated from the point of application to locations where adverse consequences, such as thrombosis, can result. Medical adhesives can be used for other purposes including, for example, the production and/or implantation of medical devices.
- the invention relates to a substrate/adhesive component composite comprising a first biocompatible substrate with a component of a medical adhesive covalently bonded to the biocompatible substrate .
- the invention in another aspect, relates to a method of securing a first biocompatible substrate to a second biocompatible substrate.
- the method comprises contacting a substrate/adhesive component composite and a remaining component of a medical adhesive to a second substrate to form an adhesive bond.
- the substrate/adhesive component composite comprises a first biocompatible substrate with a component of a medical adhesive, which is covalently bonded to the first biocompatible substrate.
- the invention in a further aspect, relates to a binding system comprising a first biocompatible substrate with a proteinaceous component of a medical adhesive forming a coating on the first biocompatible substrate, and a second medical adhesive component.
- the component coating forms following more than about one hour of contact between the proteinaceous component and the first biocompatible substrate.
- the application of the second medical adhesive component between the first substrate and a second substrate results in an adhesive bond after curing.
- the invention relates to a method of securing a first biocompatible substrate to a second biocompatible substrate. The method includes the combining of the components of a binding system to form an adhesive bond.
- the binding system comprises the first biocompatible substrate with a proteinaceous component of a medical adhesive associated with the first substrate, and a second medical adhesive component.
- the invention relates to a method of preparing a first biocompatible substrate for binding to a second biocompatible substrate. Both a component of a medical adhesive and a securing compound is applied to at least a portion of the first substrate. Securing compounds help to maintain the association between the first biocompatible substrate and the adhesive compound.
- the invention relates to a biocompatible substrate comprising a medical adhesive component incorporated into the structure components of the substrate.
- the invention relates to a method of forming a biocompatible substrate by incorporating a portion of a component of a medical adhesive with a component of the biocompatible substrate to form a blend and constructing the biocompatible substrate from the blend.
- the invention relates to a method of forming a prosthesis.
- the method includes securing a first substrate and a second substrate with a medical adhesive.
- the first substrate has an associated adhesive component, and remaining portions of the adhesive are placed between the first substrate and second substrate.
- the method can further include implanting the substrates within a patient .
- BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a schematic perspective view of a substrate joined to native tissue with a medical adhesive.
- Fig. 2 is a schematic perspective view of a substrate with a component or components of a multicomponent medical adhesive, associated with a portion of the substrate.
- Fig. 3 is a perspective view of a testing arrangement for measuring shear tear strength of an adhesive bond.
- Fig. 4 is a histogram plot of average shear break strengths measured for five different types of substrates.
- a component of the medical adhesive is associated with a biocompatible substrate prior to the application of the remaining portion of the adhesive.
- the substrate with a component of the medical adhesive is secured to a natural tissue or other biocompatible substrate using another component of the medical adhesive.
- the substrate with an associated medical adhesive component (s) can form part or all of a medical device, such that the medical adhesive can be used to attach the medical device to a support substrate, which can be native tissue or a second biocompatible material to be incorporated into a medical device.
- the adhesives described herein are useful for the attachment of a substrate to native tissue, the adhesives can be used also to attach two substrates to each other before or during implantation of the substrates into a patient .
- the adhesives can be used to reduce the number of sutures and staples that are required during surgery with a corresponding savings in time and surgical complexity.
- the adhesives can be particularly useful for the attachment of small components of a medical device that are difficult to secure with suture, staples and the like.
- an adhesive to repair wounds in soft tissue is desirable due to its potential sealing properties and uniform stress distribution.
- Initial association of a component (s) of the medical adhesive with a first substrate prior to attachment to a tissue or second substrate can result in improved tear strengths in the resulting adhesive bond.
- association of a component of the medical adhesive with a substrate decreases the likelihood that portions of adhesive will separate from the adhesive bond and circulate within the patient.
- a component of the medical adhesive is covalently attached to a substrate.
- a component of the adhesive is incorporated within a substrate during the formation of the substrate . Referring to Fig.
- the overall arrangement of the resulting structure 100 has native tissue 102 bound to a substrate 104 with a medical adhesive 106 between substrate 104 and native tissue 102.
- a portion of the tissue 102 forms a seal or adhesive bond with the substrate 104 or a portion of the substrate 104.
- a substrate other than tissue could be used instead of tissue 102.
- a component 108 of the medical adhesive is preferably applied first to substrate 104 either as a coating, by covalent binding or by incorporation into the matrix of the substrate.
- the tissue adhesives described herein can be used for the formation and/or implantation of prostheses, such as a surgical patch.
- a substrate with a component of the adhesive, is secured over a wound site by the placement of the remaining portions of the adhesive either on the tissue where the substrate is to be placed, or on the substrate over the previously applied first component of the adhesive, such that the substrate adheres to the tissue upon contact and curing.
- the patch can include multiple layers. The multiple layers can be applied sequentially to the wound, or they can be adhered either completely or partially to each other prior to application to the wound. The layers may be pieced together. Generally, the top layer of the patch may be the same size or larger than the underlying layers.
- the medical adhesive can be used to fasten the layers together and/or to bind the patch to the wound site.
- the layers can be formed from tissue, such as pericardial tissue, or a synthetic material .
- the medical adhesive can be used to attach a prosthetic device to the natural support tissue within a patient.
- a portion of the prosthetic device is formed from a substrate with an associated component (s) of the adhesive, although all of the device may be associated with the adhesive component (s) .
- the remaining portion of the adhesive can be added to the surface of the prosthesis with the first adhesive component or to the natural support tissue.
- the prosthesis is attached to the support tissue.
- a cardiac prosthesis such as a heart valve prosthesis or an annuloplasty ring, can be secured to the corresponding natural support tissue (i.e., annulus) within the patient using the medical adhesive of the invention.
- the adhesive preferably presents an interface between the first substrate and second substrate with suitable porosity and hydrophilicity .
- the adhesive interface should be sufficiently porous such that the adhesive can incorporate into or with the biocompatible material to achieve mechanical interlocking between the substrate and the adhesive.
- an adhesive interface between a tissue and a biocompatible substrate should be sufficiently hydrophilic such that the adhesive will wet the substrate, allowing complete contact between substrate, adhesive and tissue and formation of a secure bond.
- Suitable multiple component medical adhesives can include synthetic compounds, natural materials or a combination thereof.
- Suitable synthetic compound components of a medical adhesive include, for example, urethane based polymers .
- Suitable natural material components of a medical adhesive include, for example, a variety of proteinaceous materials and associated binding agents.
- one or more components of the medical adhesive are a natural material, such as a protein, while one or more components are synthetic compounds, such as a crosslinking agent.
- the medical adhesive is bioresorbable such that the adhesive is resorbed by the patient under natural physiological conditions after a suitable period of time. The period for resorption of the adhesive should be compatible with the time for the natural healing process.
- one or more components of the medical adhesive may be resorbable such that the adhesive is effectively absorbed by the patient over time.
- natural healing processes eventually provide association of the substrate with natural tissue by way of extracellular structures that take the place of the adhesive. Once the adhesive is resorbed, any potential alterations of the mechanical properties of the tissue caused by the adhesive are replaced by more natural mechanical properties of healed natural tissue.
- the substrate with the associated component of the medical adhesive is prepared prior to the final application of the remaining portions of medical adhesive. Suitable timing for the application of the associated component of the medical adhesive to the substrate depends on the stability of the adhesive component once applied to the substrate.
- the remaining portions of the medical adhesive are generally applied shortly before forming the seal or adhesive bond between the substrate and a second substrate. Then, the adhesive bond is formed, and the adhesive bond is held together while the medical adhesive cures sufficiently to secure the adhesive bond.
- Prostheses for attachment with a medical adhesive generally include a tissue substrate or a synthetic substrate at least as a portion of the prosthesis.
- the substrate is suitable for attachment or association of a component of a medical adhesive.
- the prostheses are designed for implantation into or onto a patient for extended periods of time.
- Prostheses include, for example, prosthetic hearts, prosthetic heart valves, annuloplasty rings, vascular and structural stents, vascular grafts or conduits, pledgets, suture, leads, permanently in-dwelling percutaneous devices, vascular or cardiovascular shunts, dermal grafts for wound healing, surgical patches, neurological growth supports, and bone replacement grafts, such as joint replacement prostheses.
- a surgical patch, as well as other prostheses, may be fully bioresorbable such that the entire surgical patch is resorbed by the patient after a period of time.
- Biomedical devices that are designed to dwell for extended periods of time within a patient are also suitable for use with medical adhesives . These devices include, for example, Hickman catheters.
- Substrates Appropriate biocompatible substrates can be formed from natural materials, synthetic materials or combinations thereof. Natural, i.e., biological, material for use in the invention includes relatively intact living tissue, decellularized tissue and recellularized tissue.
- tissues may be obtained from, for example, natural heart valves, portions of natural heart valves such as aortic roots, walls and leaflets, pericardial tissues, such as pericardial patches, connective tissues, bypass grafts, tendons, ligaments, skin patches, blood vessels, cartilage, dura mater, skin, bone, fascia, submuco ⁇ a, umbilical tissues, and the like.
- pericardial tissues such as pericardial patches, connective tissues, bypass grafts, tendons, ligaments, skin patches, blood vessels, cartilage, dura mater, skin, bone, fascia, submuco ⁇ a, umbilical tissues, and the like.
- Natural tissues are derived from a selected animal species, typically mammalian, such as human, bovine, porcine, seal, equine, canine or kangaroo. These natural tissues generally include collagen- containing material . Natural tissue is typically, but not necessarily, soft tissue. Tissue materials are particularly useful for the formation of tissue heart valve prostheses. The tissue can be living tissue, decellularized tissue or recellularized tissue. Decellularization approaches are described, for example, in U.S. Patent 5,855,620, incorporated herein by reference, and in published PCT Applications WO96/32905 and WO 96/03093, both incorporated herein by reference.
- Tissues can be fixed by crosslinking.
- Fixation provides mechanical stabilization, for example, by preventing enzymatic degradation of the tissue.
- Glutaraldehyde or formaldehyde is typically used for fixation, but other fixatives can be used, such as other difunctional aldehydes, epoxides, and genipin and derivatives thereof .
- Tissues can be used in either crosslinked or uncrosslinked form, depending on the type of tissue, the use and other factors. Generally, if xenograft tissue is used, the tissue is crosslinked and/or decellularized.
- synthetic materials include, for example, polymers and ceramics.
- Appropriate ceramics include, without limitation, hydroxyapatite, alumina and pyrolytic carbon. Ceramics can be coated with a polymer, protein or other compound prior to use as a substrate, if desired.
- Appropriate synthetic materials include hydrogels and other synthetic materials that cannot withstand severe dehydration. Substrate materials can be fabricated from synthetic polymers as well as purified biological polymers.
- Appropriate synthetic polymers include without limitation polyamides (e.g., nylon), polyesters, polystyrenes, polyacrylates, vinyl polymers (e.g., polyethylene, polytetrafluoroethylene, polypropylene and polyvinyl chloride) , polycarbonates, polyurethanes, poly dimethyl siloxanes, cellulose acetates, polymethyl methacrylates, ethylene vinyl acetates, polysulfones, nitrocelluloses and similar copolymers.
- These synthetic polymeric materials can be woven or knitted into a mesh to form a matrix or substrate. Alternatively, the synthetic polymer materials can be molded or cast into appropriate forms.
- Biological polymers can be naturally occurring or produced in vitro by fermentation and the like. Purified biological polymers can be appropriately formed into a substrate by techniques such as weaving, knitting, casting, molding, extrusion, cellular alignment and magnetic alignment. For a description of magnetic alignments see, for example, R. T. Tranquillo et al . , Biomaterials 17:349-357 (1996).
- Suitable biological polymers include, without limitation, collagen, elastin, silk, keratin, gelatin, polyamino acids, cat gut sutures, polysaccharides (e.g., cellulose and starch) and copolymers thereof.
- the particular substrate for association with an adhesive component can form the entire medical device or it can form portions of the medical device.
- different substrates can be combined to form the medical device.
- a fixed, heterologous tissue heart valve can be combined with a fabric sewing cuff to form a heart valve prosthesis.
- the fixed tissue and/or the sewing cuff can be associated with one or more adhesive components.
- the adhesive component can be associated with the substrate before or after the various portions are combined into the medical device.
- the selected approaches for association of the adhesive component with the substrate or substrates may influence the order of construction of the medical device.
- Suitable medical/tissue/surgical adhesives preferably have multiple components.
- the adhesives have two components, although suitable adhesives can have more than two components.
- the medical adhesives can include various additives described in more detail below.
- the medical adhesives can include synthetic compounds, natural compositions/materials or a combination thereof.
- the medical adhesive generally should be non- toxic.
- Approaches for application of the adhesive described herein are designed to reduce or eliminate circulation of the adhesive and/or one or more of the adhesive components. Furthermore, by reducing or eliminating circulation of the adhesive or adhesive components, risks associated with potential migration of the adhesive are correspondingly reduced or eliminated.
- preferred adhesives include, for example, urethane-based polymers , copolymers, and mixtures thereof.
- Polyurethanes are ester-amide derivatives of carboxylic acids.
- Urethane oligomers/prepolymers can be formed with terminal reactive functional groups. Because of the terminal functional groups, the prepolymers are particularly suitable for the formation of crosslinked mixed polymers exhibiting a range of desirable properties generally characteristic of polyurethanes and of the other components.
- the urethane prepolymer can be used as one component of the adhesive, with a crosslinking agent or agents being the other component or components of the adhesive.
- Isocyanate (-NCO) - terminated urethane prepolymers are particularly suitable adhesive components.
- Polyurethanes including polyurethane prepolymers can be formed either by the reaction of bischloroformates with diamines or the reaction of diisocyanates with polyhydroxy compounds. The approach to urethane polymerization involving diisocyanates with polyhydroxy compounds can be used to produce urethane prepolymers with isocyanate functional groups at their terminus .
- Suitable urethane prepolymers can be formed by the reaction of polyisocyanates with polyols .
- Suitable polyisocynates include, for example, aromatic polyisocyanates containing 6-20 carbon atoms excluding the -NCO groups, such as o-, m- and p- phenylene diisocyanates (PDI), 2,4- and 2,6-tolulene diisocyanates (TDI), diphenylmethane-2 , 4 ' and 4,4'- diisocyanates, diphenylmethane 2-4'- and 4,4'- diisocyanates (MDI), naphthalene-1 , 5-diisocyanate, triphenylmethane 4, 4' , 4"- triisocyanate, polymethylenepolyphenylenepolyisocyanates (PAPI ) obtained by phosgenation of aniline-formaldehyde condensation products, m- and p-isocyanato-phenyl sulfonyl isocyanate, and the like; aliphatic polyisocyanates containing 2
- TDI TDI
- MDI long with 4,4'- and 2,4' -isomers and mixtures isomers with MDI or PAPI
- PPDI p-PDI
- Alternative preferred embodiments include combinations of PPDI with a minor amount (usually up to about 50% by weight, preferably up to about 30% by weight) of one or more other polyisocyanates, such as aromatic polyisocyanates, particularly TDI, MDI, modified MDI and mixtures thereof.
- the other polyisocyanates are reacted at early stages of prepolymer production so as to provide PPDI terminated prepolymers .
- Suitable polyols for the formation of the prepolymers include hydrophilic polyether polyols, other polyols and mixtures thereof.
- hydrophilic polyether polyols include adducts of ethylene oxide (hereinafter EO) or combinations of EO with other alkaline oxide (s) (hereinafter AO) formed with one or more compounds containing at least two active hydrogen atoms, such as polyhydric alcohols, polyhydric phenols, amines, polycarboxylic acids, phosphorous acids and the like.
- EO ethylene oxide
- AO alkaline oxide
- active hydrogen atoms such as polyhydric alcohols, polyhydric phenols, amines, polycarboxylic acids, phosphorous acids and the like.
- Suitable polyhydric alcohols include dihydric alcohols, such as ethylene glycol, propylene glycol, 1,3- and 1,4 -butane diols, 1,6-hexane diol, neopentyl glycol, diethylene glycol, bis (hydroxymethyl) cyclohexane, bis (hydroxyethyl) benzene, hydrogenated bisphenol A, hydrogenated bisphenol F, polytetramethylene glycols, polyester diols and silanol- terminated polysiloxanes ; trihydric alcohols, such as glycerol, trimethylol propane, trimethylol ethane, 1 , 2 , 3 , -butane triol, 1,2,6-hexane triol and polyester triols; and polyhydric alcohols having 4-8 or more hydroxyl groups, such as pentaerythritol, diglycerol, alphamethylglucoside, sorbitol, xylitol,
- polyhydric phenols include mono- and poly-nuclear phenols, such as hydroquinone, catechol, resorcin, pyrogallol, and bisphenols such as bisphenol F, bisphenol S and the like, as well as phenol-formaldehyde condensation products.
- Suitable amines for the formation of polyether polyols include ammonia; alkanol amines, such as mono-, di- and tri-ethanol amines, isopropanol amines and the like; aliphatic, aromatic, araliphatic and alicyclic monoamines, such as C-,-C 20 alkyl amines (methyl, ethyl, isopropyl, butyl, octyl and lauryl amines, and the like) , aniline, toluidine, naphthyl amines, benzyl amine, cyclohexyl amine and the like, aliphatic, aromatic, araliphatic and alicylic polyamines, such as C 2 -C 5 alkylene diamines (ethylene diamines) , diethylene triamine, toluene diamines, phenylenediamines, xy ly 1 ene d i amine s , methylene
- Suitable AO for use in combination with EO for producing polyether polyols, include, for example, propylene oxide [hereinafter PO] , 1,2-, 2,3-, 1,3- and 1,4-butylene oxides, styrene oxide, epichlorohydrin and the like, as well as combinations thereof.
- Preferred AO include PO .
- addition of EO, or a combination of EO with an AO, to active hydrogen atom-containing compounds can be performed in conventional ways, with or without catalysts, such as alkaline catalysts, amine catalysts and acidic catalysts, under atmospheric pressure or at an elevated pressure, in a single step or in multiple steps.
- catalysts such as alkaline catalysts, amine catalysts and acidic catalysts
- Addition of EO and AO may be performed by random-addition, block-addition or combination thereof, such as random-addition followed by block-addition. Random-addition is the preferred approach.
- Hydrophilic polyether polyols have an equivalent weight (molecular weight per hydroxl group) generally from about 100 to about 5,000, preferably from about 200 to about 3,000, and an oxyethylene content of generally at least about 30%, preferably from about 50% to about 90% by weight.
- Polyether polyols having an equivalent weight higher than 5,000 can be too viscous, while use of polyether polyols with an equivalent weight less than 100 can result in an adhesive with insufficient flexibility.
- Polyether polyols of oxyethylene content less than about 30% by weight, having insufficient hydrophilic nature, can have a slow cure rate and poor bonding power with water-rich tissue.
- Content of the primary hydroxyl groups of polyether polyols is preferably at least about 30%, more preferably at least about 50%, and most preferably at least about 70%.
- polyols optionally used in conjunction with hydrophilic polyether polyols, include low molecular weight polyols and/or hydrophobic polyols.
- polyols are polyhydric alcohols described above as reactants for forming hydrophilic polyether polyols, AO adducts (such as PO adducts) of these polyhydric alcohols or other active hydrogen atom- containing compounds, and polyester polyols.
- Suitable polyester polyols include, for example, condensation products of dihydric and/or trihydric alcohols, such as ethylene glycol, propylene glycol, 1,3- and 1,4 -butane diols, 1,6-hexane diol, neopentyl glycol, diethylene glycol, glycerol, trimethylolpropane and the like, and/or polyether polyols, such as those described above, with dicarboxylic acids, such as aliphatic or aromatic dicarboxylic acids, including, for example, glutaric acid, adipic acid, 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 and phthalic anhydrides, dimethyl terephtharate, and the like, and ring-opening polymerization products of lactones,
- Preferred polyols for producing NCO-terminated urethane prepolymers have an average equivalent weight from about 100 to about 5,000, more preferably from about 200 to about 3,000 and generally 2-8 hydroxyl groups, preferably 2-4 hydroxyl groups.
- the polyisocyanate and polyol preferably are mixed with a ratio of NCO/OH of about 1.5 to about 5.0 and more preferably from about 1.7 to about 3.0.
- the resulting prepolymers preferably have an NCO-content from about 1% to about 10% by weight and preferably about 2% to about 8% by weight. Lower NCO-contents can result in a low binding strength and higher NCO-contents can lead to brittle bonds.
- the polyisocyanates and polyols react to form urethane prepolymers.
- These prepolymers are moderate molecular weight oligomers.
- the size of the oligomers is controlled by the relative amounts of NCO functional groups and OH functional groups. Since the NCO functional groups are added in excess, the polymerization terminates when all of the OH groups have reacted. The unreacted NCO groups form the basis for further polymerization to form the final adhesive.
- Bioresorbable urethane based adhesives can be made from suitable hydrophilic urethane prepolymers.
- the urethane prepolymers are formed from an organic polyisocyanate and polyester polyol derived from a dicarboxylic acid with the formula HOOC - (A) m - COOH where m is 0 or 1 and A is -CH 2 - or an electron attracting group represented by the formula -R-CO- or
- R is a divalent hydrocarbon group containing 1- 8 carbon atoms
- R' is a divalent hydrocarbon group or halogen-substituted hydrocarbon group containing 1-20 carbon atoms
- X is a halogen atom or nitro or cyano group
- Y is a hydrogen atom, a halogen atom or nitro or cyano group
- n is 0, 1 or 2.
- Suitable compositions for the second component of the urethane based medical adhesives include polyols, such as the polyols used to form the prepolymer.
- the amount of polyols added can be based on the number of functional groups remaining unreacted in the urethane prepolymer.
- the second component of the urethane oligomer adhesive can be an unsaturated cyano compound containing a cyano group attached to a carbon atom involved in the polymerizable double bond, such as cyano acrylic acids and esters thereof.
- Examples of these unsaturated cyano compounds include, for example, cyanoacrylic acid, cyano methacrylic acid, methyl cyanoacrylic acid, methyl cyanomethacrylic acid, ethyl cyanoacrylic acid, ethyl cyanomethacrylic acid, isobutyl cyanoacrylic acid, isobutyl cyanomethacrylic acid, corresponding esters, a c r y 1 on i t r i 1 e s , methacrylonitriles, cyanoacrylonitriles, cyanomethacrylonitriles and mixtures thereof.
- Such adhesives are described in U.S. Patent 4,740,534 to Matsuda et al .
- the urethane based adhesive composition generally comprises about 20 to about 90 percent by weight urethane prepolymer and preferably about 30 to about 70 percent by weight urethane prepolymer.
- the ratio of urethane prepolymer to unsaturated cyano compound can be varied to achieve a desired hardness. The use of a higher percentage of urethane prepolymer results in an adhesive with greater flexibility.
- a catalyst can be added if desired.
- Adhesives based on components that are natural compositions generally are based on inherent natural binding affinities and corresponding biological responses.
- one or more components of the adhesive is a protein or protein based compound.
- Protein is intended to be interpreted broadly in terms of any compound with a polypeptide (i.e., amino acid) component, and may include derivatives of natural proteins and polypeptides with additional covalently or non-covalently attached components, such as additional polypeptides, nucleotides, carbohydrates, and other organic or inorganic compounds.
- Protein components generally contain amino acids with side chains with functional groups useful for binding with the remaining adhesive components.
- an adhesive component can replace functional groups that had been eliminated in the tissue substrate by reactions during the crosslinking process.
- Fibrinogen also known as factor I
- the protein thrombin removes one or two peptides from fibrinogen to form fibrin.
- Thrombin is also involved in the blood clotting process.
- fibrin adhesives have been based on the crosslinking of fibrin. Fibrin glues generally involve combinations of fibrinogen, thrombin and Factor XIII. Factor XIII also is involved in the natural wound healing mechanism. Factor XIII, also known as fibrin stabilizing factor, is activated by thrombin, and converts soluble fibrin to an insoluble clot.
- Fibrin adhesives polymerize and also covalently crosslink with collagen and other tissue components to form a liquid tight bond. If fibrinogen, thrombin or factor XIII are associated with a substrate as a component of the adhesive, the additional portions of the adhesives can include additional amounts of these compounds. The final amounts of the fibrinogen, thrombin or factor XIII components in the complete adhesive can be adjusted, as desired, to yield selected adhesive pro ⁇ erties, such as strenqth and/or cure times, or for convenient application.
- Non-aqueous adhesive includes a biological component and a synthetic component.
- the biological component includes a protein.
- gelatin-resorcinol aldehyde adhesives involve a gelatin- resorcinol material that is formed by heating gelatin and resorcinol .
- Gelatin is formed by hydrolytic activity on collagen protein.
- Formaldehyde, glutaraldehyde or the like can be used to crosslink the gelatin-resorcinol material to complete the formation of the glue .
- a similar adhesive is formed from water soluble proteinaceous material and di- or polyaldehydes .
- the proteinaceous materials may be purified proteins or mixtures of proteins.
- Preferred proteins include albumins, including ovalbumins .
- Particularly preferred proteins include serum albumins of human or animal origin.
- Suitable water soluble di- or polyaldehydes include glyoxal and glutaraldehyde .
- the adhesive cures within a minute or less after the application of the aldehyde by spraying a layer over a coating of the proteinaceous material .
- Such adhesives are described further in U.S. Patent 5,385,606 to Kowanko, incorporated herein by reference.
- the proteinaceous material preferably includes serum albumin as a primary component .
- the second component includes bifunctional crosslinking agents, with preferred crosslinking agents including polyethylene glycol with a molecular weight ranging from about 1,000 to about 15,000.
- the polyethylene glycol can be modified to incorporate leaving groups to activate the crosslinking agent to bind at primary or secondary amines of the proteins .
- Suitable leaving groups include, for example, succinimidyl , maleimidyl, phthamimidyl , other imides, heterocyclic leaving groups such as imidazolyl, aromatic leaving groups such as nitrophenyl, and fluorinated alkylsulfone leaving groups such as tresyl (CF 3 -CH 2 S0 2 -0- ) .
- a linking group can be bonded between the polyethylene glycol and the leaving group .
- the adhesives can contain additives to modify the mechanical properties of the adhesive.
- Suitable additives include, for example, fillers, softening agents and stabilizers.
- Representative fillers include, for example, carbon black and metal oxides, silicates, acrylic resin powder, and various ceramic powders.
- Representative softening agents include, for example, dibutyl phosphate, dioctylphosphate, tricresylphosphate, tributoxyethyl phosphates and other esters.
- Representative stabilizers for the urethane based polymers include, for example, trimethyldihydroquinone, phenyl- ⁇ -naphthyl amine, p-isopropoxydiphenylamine , diphenyl-p-phenylene diamine, and the like.
- the protein based adhesives can also contain sugars such as glycine, glucose or sucrose to improve solubility, and stabilizers, including heparin.
- Fibrin glues can r-nntain additional components, such as an inhibitor of fibrinolysis (anti-fibrolytic agents), for example, aprotinin and/or transexamic acid, with calcium chloride .
- One or more components of the adhesive generally are associated with at least a section of the substrate. While the associated components can include more than one component, the associated components necessarily lack at least one necessary component in the formation of the adhesive. In other words, the associated component or components do not form an entire adhesive by themselves, in the sense that upon addition of other components, a strong adhesive bond is formed.
- the adhesive components associated with the substrate can be applied as a coating, bound covalently to the substrate, and/or incorporated into the substrate matrix or structure .
- the additional portions of the adhesive include all adhesive components and additives that are not initially associated with the substrate.
- the additional portions of the adhesive can include additional quantities of the associated adhesive components.
- the additional portions of the adhesive can be added, for example, as a coating or by covalent binding, onto a native tissue surface or second substrate to be joined with the substrate, or applied over a section of the substrate associated with the adhesive components. Once all of the portions of the adhesives have been applied, the substrate is joined with native tissue to bind the substrate to the native tissue.
- the adhesive bond has an adhesive strength at least about three times greater than that exhibited by the one or more associated components adhered to the tissue without the additional portions. While the substrate generally is adhered to native tissue, the substrate can be bound to a second substrate before or during the process of implanting a medical device.
- the multiple substrates adhered to each other with the medical adhesive are implanted in a patient prior to, during or after complete curing of the adhesive.
- the attachment of the substrates to each other using the procedures herein has the same advantages with respect to localization of the adhesive and generally increased bonding strength.
- the component or components associated with the substrate can be selected for the ability to associate with the substrate without losing the ability to bind with the remaining portions of the adhesive.
- the urethane prepolymers generally can be associated with the substrate.
- the protein generally can be associated with the substrate. If desired, one portion of the substrate can include associated components of one adhesive while other portions of the substrate can include associated components of another adhesive. The two portions with different associated components can overlap partially or completely, if desired.
- the adhesive components are associated with the substrate such that large numbers of adhesive molecules are not easily dissociated from the substrate over the period of time required for curing of the adhesives.
- the direct application of the adhesive component (s) as a coating over the selected portion of the substrate is sufficient to provide sufficiently strong association.
- the strong association of an adhesive component coating can be due to natural attractions between the substrate material and the adhesive component, natural wetting effects of the adhesive component on a surface, the lack of solubility of the adhesive component in an aqueous solution and/or other similar effects.
- the associated adhesive components can be associated with the substrate by covalent bonding or by application of a coating.
- a component coating is stable for some period of time, preferably days or longer under proper storage.
- the component coating forms following at least an hour, and in some cases following two hours or more, of contact between the adhesive component (s) and the substrate, such that the adhesive component can fully associate with the surface of the substrate through various non-covalent interactions.
- the substrate with the associated adhesive component (s) generally is prepared and stored prior to its intended use .
- the substrate can be placed in a solution containing the adhesive component.
- the adhesive components can be brushed onto the surface, administered from an applicator or sprayed on as an aerosol or the like.
- the associated adhesive components can be incorporated into the matrix of the substrate.
- the method can be selected to be suitable for the substrate material and the adhesive components.
- the adhesive component can be added to the substrate and dried to remove the solvent.
- the adhesive components can be applied as a concentrated solution, with the resulting composite being kept moist to prevent the substrate/adhesive component composite from drying out .
- a suitable container for the storage of moisture sensitive substrate/adhesive component composites is described in PCT/US98/03519 , entitled “Storage Container,” incorporated herein by reference.
- a component of the medical adhesive is covalently linked with the substrate.
- the covalently linked adhesive component is a protein
- tissue crosslinking agents can be used for the covalent binding, such as difunctional aldehydes, including glutaraldehyde.
- Crosslinking agents bind to the protein in the adhesive component and to proteins in the tissue substrate .
- suitable crosslinking agents can be used for the covalent binding. Molecules of the crosslinking agent have one or more functional groups active to bind with the adhesive component and one or more functional groups to bind with the substrate.
- Suitable substrates have functional groups capable of chemical crosslinking. Based on the nature of the material in a synthetic substrate, a suitable functional group in the crosslinking agent can be selected. The functional group of the crosslinking agent would be identifiable as a functional group that can chemically crosslink with the synthetic polymer.
- chlorosulfonated polyethylene as a substrate material, can react with crosslinking compounds having alcohol or amine groups.
- a compound having both an aldehyde functional group and an alcohol or amine functional group can crosslink between a protein adhesive component and a chlorosulfonated polyethylene substrate.
- a polystyrene substrate can react with halogenated hydrocarbons.
- a suitable crosslinking agent to bind a protein to a polystyrene substrate would have an aldehyde functional group and a halogenated methyl group.
- the bonding conditions can be adjusted to covalently bond a desired amount of the adhesive component without inactivating the adhesive ability of the component.
- concentrations of the binding agent and the adhesive component can be adjusted.
- a protein adhesive component generally has a concentration in a bonding solution from about lng protein/ml to about 50 ⁇ g protein/ml and preferably from about 25ng/ml to about lOO ⁇ g/ml. The selection of suitable concentrations can be evaluated empirically.
- crosslinking agent For the bonding of a protein adhesive component to a tissue substrate, bonding with a crosslinking agent can be performed under carefully controlled conditions to avoid inactivating the adhesive properties of the adhesive component.
- the crosslinking is preferably performed with a dilute solution of crosslinking agent, such as glutaraldehyde.
- Crosslinking preferably is performed with a concentration of crosslinking agent less than about 0.1% crosslinking agent, more preferably less than about 0.05% crosslinking agent and even more preferably from about 0.005% to about 0.02% crosslinking agent.
- percent values are based on a volume per volume dilution of a concentrated volume percent glutaraldehyde stock solution, generally a fifty percent (50%) by volume stock solution.
- the crosslinking of a protein adhesive component to a tissue substrate can be performed for at least about 5 minutes and generally is performed for about 15 minutes to about 24 hours or longer.
- glutaraldehyde crosslinking of certain proteins to tissue substrates it has been observed that the extent of binding levels off relatively quickly with respect to crosslinking time, see copending and commonly assigned U.S. Patent application, serial number 09/186,810, entitled “Prostheses With Associated Growth Factors,” incorporated herein by reference.
- Preferred crosslinking times can be evaluated empirically based on the disclosure herein. Under the preferred mild conditions described herein, a tissue substrate generally is not significantly fixed by the crosslinking agent .
- the solution containing the adhesive component preferably is buffered at a near physiological pH ranging from about 6.0 to about 8.5, and more preferably ranging from about 6.9 to about 7.5.
- Suitable buffers can be based on, for example, the following compounds: phosphate, borate, bicarbonate, carbonate, cacodylate, citrate, and other organic buffers such as tris (hydroxymethyl) aminomethane (TRIS), N- (2-hydroxyethyl) piperazine-N' - ( 2 - ethanesulfonic acid) (HEPES) , and morpholine propanesulphonic acid (MOPS) .
- TMS tris (hydroxymethyl) aminomethane
- HEPES N- (2-hydroxyethyl) piperazine-N' - ( 2 - ethanesulfonic acid)
- MOPS morpholine propanesulphonic acid
- photochemical coupling can be used to induce covalent coupling of an adhesive component to the substrate.
- Photochemical coupling is based on the use of high energy light, e.g., ultraviolet light, to form reactive intermediates of certain functional groups. These reactive intermediates can form carbon-carbon bonds between two compositions. Aryl ketone functional groups are particularly useful in this respect.
- a crosslinking agent may not be needed to covalently bond the adhesive component to the substrate.
- Photochemical coupling can be used for attachment of protein adhesive components to a tissue substrate. See, for example, Dunkirk et al . , J. Biomaterials Applications 6 : 131-156 (1991), incorporated herein by reference.
- the tissue may or may not be separately crosslinked since the photochemical coupling generally also crosslinks the tissue, i.e., photofixation.
- photochemical coupling can be used to attach a linker to the tissue either before, after, or during binding of the linker to a protein adhesive component.
- Ultraviolet light can also be used to crosslink various synthetic polymers to a substrate. Specifically, vinyl polymers crosslink when exposed to radiation due to a free radical mechanism.
- a crosslinking agent can be used with a group known to photoactivate .
- a variety of polymer side groups are known to be photoactive including, for example, alkyne, anthracene, benzothiophene dioxide, chalcone, cinnamate, coumarin, dibenzazepine, diphenylcyclopropene carboxylate, episulfide, maleimide, stilbazole, stilbene, styrene, 1 , 2 , 3-thiadiazole, and thymine .
- the substrate polymer and/or the adhesive component can include these groups that may undergo photoactivation.
- the medical adhesive component can be incorporated into the structure/matrix of a biocompatible substrate when the substrate is formed.
- an amount of the medical adhesive component can be mixed with the components of the substrate to form a blend.
- the substrate includes within its structure the molecules of the medical adhesive component.
- a portion or all of the resulting substrate includes the medical adhesive component distributed through the matrix of the substrate.
- the biocompatible substrate can include several portions and/or layers such that the medical adhesive component is only distributed within a subset of the portions and/or layers of material that form the biocompatible substrate.
- Polymer substrates can be formed by conventional polymer processes.
- the polymer can be synthetic polymers or natural polymers, such as purified collagen.
- the substrate materials can be selected such that the surgical glue component is not decomposed by the processing.
- a substrate formation process can be selected that does not require the addition of the adhesive component to a hot substrate material.
- a solvent casting process or the like can be used instead of a thermal molding process.
- the concentration of the adhesive component can be selected empirically to provide sufficient adhesion upon addition of the remaining portions of the adhesive and completion of the adhesive bond with the native tissue or other substrate .
- E Formation of the Adhesive Bond
- the additional portions of the adhesive can be added in a variety of ways.
- the additional portions of the adhesive can be applied directly to the portion of native tissue or second substrate to which the first substrate is applied.
- the second substrate may or may not include an associated adhesive component (s) .
- the additional portions of the adhesive can be applied over the substrate with the associated adhesive components prior to contacting the substrate with the native tissue or second substrate for attachment.
- the additional portions of the medical adhesive can be brushed onto the surface, administered from an applicator, applied by dipping the appropriate substrate into a solution comprising the additional portions, or sprayed on as an aerosol or the like.
- the consistency of the additional portions of the medical adhesive may indicate which approaches for its application are particularly suitable.
- the additional portions of the adhesive generally include one or more additional adhesive components that are not included in the adhesive components associated with the substrate.
- the additional portions of the adhesive can include additional quantities of the adhesive component or components that are associated with the substrate.
- the additional portions of the adhesive can include additives .
- the formation of the adhesive bond involves the joining of the different components of the adhesive. If the additional portions of the adhesive are applied over the substrate at the location of the associated component (s) of the adhesive, the resulting structure is distinguishable from the application of a coating of the adhesive since the adhesive forms layers of components with the components in the undermost layer incapable of forming an adhesive alone. Thus, in either approach for the application of the additional portions of the adhesive, the resulting structure of the substrate and adhesive is distinct from the addition of a coating of a fully blended adhesive, including all components within the blended adhesive.
- the additional portions of the adhesive are added just prior to the forming of the interface, although the precise timing can be adjusted based on a variety of factors. Relevant timing factors include cure rate, the timing of the surgical procedure, and the stability of the separate components under the environmental conditions, such as humidity, to which they are applied. Preferred adhesives have cure times ranging from about 1 minute to about 5 hours, more preferably from about 5 minute to about 1 hour, and even more preferably from about 5 minutes to about 30 minutes. After the application of the remaining portions of the medical adhesive, the substrate is contacted with native tissue or a second substrate at the desired point of attachment . A variety of approaches can be used to hold the substrate to the native tissue or second substrate while the adhesive cures sufficiently.
- the adhesive has cured sufficiently when the adhesive bond can hold against standard stresses applied to the adhesive bond without the need for additional support.
- Standard stresses can vary over significant ranges. For example, the stresses can be relatively low for adhesives holding a surgical patch or higher for adhesives securing a heart valve prosthesis. When fully cured, the adhesive reaches levels of strength for the adhesive bond to meet expected durability requirements.
- a health care professional can hold or maintain the substrate in place long enough to reach sufficient curing.
- clamps, clips or the like can be used to hold the substrate in place.
- These approaches can be used with adhesives having reasonably rapid cure rates.
- a few suture stitches or staples can be applied to hold the substrate in place.
- a suitable degree of suturing or stapling generally would be considerably less using the medical adhesive than the degree of suturing or stapling required if the suture or staples were providing the primary support for the attachment of the substrate.
- the limited use of suture and/or staples are intended to provide stabilization to the adhesive bond at the early stages of curing to prevent tearing of the adhesive bond.
- a junction, seal or adhesive bond is formed between the substrate and the native tissue or other substrate with at least a portion of the surgical glue between the substrate and the native tissue or other substrate.
- the presence of an adhesive bond does not imply anything about the characteristics of the connection at the point of attachment between the native tissue/second substrate and first substrate.
- the junction can involve a "seamless joining" of the native tissue/second substrate to the first substrate in the sense of a smooth connection between the two materials.
- the adhesive bond includes the overlapping region with the adhesive between the first substrate and the tissue or other substrate.
- the adhesive bond preferably has a bond strength of at least about 75 g/cm 2 and more preferably at least about 100 g/cm 2 . Since it is not possible to measure the bond strength of an actual adhesive bond in a patient, the bond strength refers to a comparable adhesive bond formed between an equivalent section of substrate and a piece of tissue that corresponds to and is roughly equivalent to the native tissue in the actual adhesive bond. Referring to Fig.
- the bond strength is measured by forming an adhesive bond 150 at overlapping edges of a portion of substrate 152 and a section of fresh tissue 154, i.e., nondegraded tissue without fixation, such that substrate 152 and tissue 154 extend in opposite directions from the adhesive bond 150.
- a different substrate can be used instead of the tissue, as appropriate.
- the edges extending away from the adhesive bond are held between clamps 160, 162, 164, 166.
- Adhered substrates 152, 154, positioned between clamps 160, 162, 164, 166, are pulled, as shown in Fig. 3, in the respective direction in which they extend from the adhesive bond 150 until the adhesive bond ruptures under the shear forces .
- the value of the shear force (tear strength) applied when the adhesive bond breaks divided by the area of the adhesive bond is a measure of the bond strength. While actual adhesive bonds may not be planar, i.e., flat, the bond strengths are evaluated as planar adhesive bonds for consistency.
- the bond strengths of nonplanar adhesive bonds generally should be roughly equal to the area of the adhesive bond multiplied by the planar bond strength per area if a good hemostatic or liquid tight seal is formed around the adhesive bond.
- the adhesive is resorbed preferably over a time period during which the substrate and tissue are joined together during natural healing processes.
- the adhesive is replaced by natural tissue without compromising the integrity of the adhesive bond.
- Variations in the resorption rate can be adjusted empirically to ensure that the adhesive remains at least for sufficient periods of time so that the strength of the adhesive bond is not compromised.
- the length of time for the wound to heal can depend significantly on the size of the wound and on the stresses to which the wounded tissue is subjected. For example, tissue subjected to little stress may heal sufficiently after a few days, while tissue subjected to considerable stress may require a considerably longer period of time.
- the adhesive can contain biological response modifiers. Inclusion of the biological response modifiers within the adhesive can result in the gradual release of the biological response modifier, especially if the adhesive is bioresorbable .
- Suitable biological response modifiers include, for example, antimicrobial agents, anticalcification agents and growth factors.
- the additives are combined with the additional portions of the adhesive that are applied topically, although protein additives can be combined with the adhesive components that are associated with the substrate if the association process would also associate the protein additives with the substrate.
- Antimicrobial agents include, for example, antibiotic organic chemical agents and antimicrobial metal ions.
- Organic antibiotic agents include, for example, penicillin and the like.
- Antimicrobial metal ions include, for example, ions of Ag, Au, Pt, Pd, Ir, Cu, Sn, Sb, Pb, Bi, Zn and combinations thereof.
- the prosthesis or a portion of the prosthesis can be soaked in a solution of the antimicrobial metal ions, such as a silver nitrate solution.
- the solution can be sprayed, brushed or similarly applied to the substrate.
- antimicrobial metal ions can be applied in the form of an antimicrobial metal salt with a relatively low solubility in aqueous solutions.
- Silver 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, cupric stearate and cupric phosphate.
- Suitable zinc compounds include, for example, zinc stearate and zinc phosphate.
- suitable palladium compounds include, for example, palladium acetate .
- Patent Application serial number 08/974,992 to Ogle entitled “Medical Article with Adhered Antimicrobial Metal,” incorporated herein by reference.
- Antimicrobial metal ions can be delivered using exogenous storage structures, as described in copending and commonly assigned U.S. Patent application 08/787,139 to Tweden et al . , entitled “Silver Delivery System,” incorporated herein by reference.
- Certain polyvalent metal ions are effective at reducing calcification of prostheses.
- Preferred anticalcific metal ions include, for example, aluminum ions (AIM and ferric ions (Fe +3 ) .
- Other suitable metal ions include, for example, manganese ions, zinc ions, gallium ions, lanthanum ions and beryllium ions.
- the prosthesis or a portion of the prosthesis can be soaked in a solution of the anticalcific ions.
- a solution of the anticalcific ions for example, an aluminum nitrate or ferric nitrate can be used.
- the anticalcific metal ions can be deposited as a relatively insoluble salt by the addition of a selected anion to a solution of soluble salt of an anticalcific cation in contact with a prosthesis or a portion of a prosthesis.
- aluminum palmitate can be precipitated from a solution of aluminum chloride by the addition of palmitic acid
- ferric phosphate can be precipitated from a solution of ferric chloride.
- exogenous storage structures have been shown to be useful in delivering these polyvalent cations. See, commonly assigned and copending U.S. Patent application 08/690,661 to Schroeder et al . , entitled Calcification-Resistant Biomaterials , " incorporated herein by reference. These exogenous storage structures with stored anticalcific ions can be combined with the deposits of antimicrobial elemental metal .
- the biological response modifier can be a growth factor.
- a particularly preferred growth factor includes, for example, vascular endothelial growth factor (VEGF) .
- VEGF encourages the proliferation of endothelial cells which line vascular tissue.
- VEGF is a protein that can be included with the adhesive components associated with the substrate or with the additional portions of adhesive.
- modified substrate can be stored.
- Preferred storage techniques minimize the risk of microbial contamination.
- modified substrates that are not moisture sensitive can be stored in a dry air tight container.
- the modified substrate can be stored in a sterile sealed container with an antiseptic solution. The nature of the antiseptic solution should be compatible with the substrate and maintain the activity of the adhesive component .
- a crosslinked tissue substrate with a protein adhesive component can be stored in a dilute aqueous glutaraldehyde solution. Due consideration should be given to possible loss over time of the bonded adhesive component or the efficiency of the bonded adhesive component. Additives, including antioxidants, such as ascorbic acid, can be added to the storage solution to reduce the loss of efficiency of the adhesive component during storage.
- the modified substrate can be placed in sealed and sterile containers. The containers are generally dated such that the date reflects the maximum advisable storage time considering possible degradation of the adhesive component as well as other factors. The containers are packaged along with instructions for the proper use of the substrate and along with appropriate and/or required labeling. The containers are distributed to health care professionals for use in appropriate medical procedures.
- a health care professional may rinse the substrate after removing it from the storage container just before its use.
- the remaining components of the adhesive may or may not be distributed along with the modified substrate. If the remaining components are not distributed with the modified substrate, the remaining components, in some circumstances, may be purchased as a separate adhesive product.
- the substrate can be modified at the hospital or another site remote from the production facilities.
- the modified substrate may only be stored a short period of time prior to use.
- the substrate and adhesive components needed to modify the substrate can be distributed separately or together.
- Appropriate instructions can be distributed with either the substrate, one or more of the adhesive components/portions, or combinations thereof.
- the modified substrate can be kept in the solution used for modifying the substrate.
- the modified substrate can be used immediately after completing the modification of the substrate .
- This example demonstrates increased binding strengths resulting from covalently attaching a component of a fibrin adhesive to components of a tissue bond.
- the samples were prepared from porcine aortic walls. Two pieces of aorta approximately 2 cm x 6 cm were cut from the same vessel removed from a valve. The length dimension of each piece corresponded to the radial direction of the vessel prior to cutting the sample. Twelve aorta pieces (six pairs) were crosslinked and stored for about 3 weeks in 0.5 percent glutaraldehyde in 0.9% saline (saline, Baxter Health Care Corp., Deerfield, IL) . The glutaraldehyde solution was prepared as a volume per volume dilution of a fifty percent (50%) by volume glutaraldehyde stock solution.
- aorta pieces Eighteen uncrosslinked aorta pieces (nine pairs from nine sections of aorta) were prepared. Six pieces (three pairs) were placed overnight in 50 ml of 0.9% saline. Six additional aorta pieces (three pairs) were placed overnight in solutions containing fibrin, and six other aorta pieces (three pairs) were placed overnight in a solution of fibrinogen (80% activated, i.e., clottable) . The concentrated fibrin solution was prepared by dissolving 5. Og of fibrin (fibrin from bovine blood, Sigma Chemical Company, lot 110H9304) in 100 ml 0.9% saline. Similarly, the fibrinogen solution was formed by dissolving 5.
- Og fibrinogen (Sigma Chemical, lot 64H9300) in 100ml of 0.9% saline. Then, the aorta pieces stored overnight in fibrin or fibrinogen were placed separately in a 0.5 volume percent phosphate buffered glutaraldehyde solution for two hours. After two hours in the glutaraldehyde solution, the samples were removed and incubated for one hour in 0.1 molar tris buffer (Tris Ultra Pure, tris (hydroxymethyl) aminomethane, Gibco BRL, Life Technologies, Inc., Grand Island, NY).
- Tris Ultra Pure, tris (hydroxymethyl) aminomethane Gibco BRL, Life Technologies, Inc., Grand Island, NY.
- the corresponding crosslinked or uncrosslinked pieces from the same vessel were then glued together with an adhesive. About 2 square centimeters of adhesive was applied to the surface at the end of one piece of tissue.
- the adhesive was a fibrin glue
- CA produced using 5,000 units/5ml fibrin from Park Davis, Morris Plains, NJ) , except for three pairs of pieces of crosslinked aorta (labeled CY/x-linked) that were attached with a cyanoacrylate glue, Duro ® (Super Glue, Hartford, CT) .
- the fibrin glue samples are labeled FG along with a label indicating tissue treatment - crosslinked as "x-linked", untreated as "fresh”, fibrinogen treated as "fibrinogen” and fibrin treated as "fibrin”.
- the fibrin glue was applied using a two orifice nozzle that combines the components through a single tube upon application. The samples were overlaid, and the adhesive was allowed to cure for about 20 minutes.
- the strength of the bond was tested on an Instron 50 lb Load Cell, Model Sintech l/S from the Sintech Division of MTS Systems Corporation (Research Triangle Park, NC) .
- the full width of the two joined tissue pieces were gripped in the load cell to apply an even force across the adhesive bond.
- the load that results in sufficient shear force to tear the adhesive bond was measured in a configuration approximately as shown in Fig. 3.
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP00905657A EP1146917A1 (en) | 1999-01-22 | 2000-01-19 | Medical adhesives |
JP2000594503A JP2002535046A (en) | 1999-01-22 | 2000-01-19 | Substrate / adhesive component composite |
AU27306/00A AU2730600A (en) | 1999-01-22 | 2000-01-19 | Medical adhesives |
BR0007644-9A BR0007644A (en) | 1999-01-22 | 2000-01-19 | Composite of substrate / adhesive components, method of attaching a first substrate to a second substrate, bonding system, method of preparing a first substrate for bonding to a second substrate, substrate, methods of forming a substrate and forming a prosthesis |
CA002358565A CA2358565A1 (en) | 1999-01-22 | 2000-01-19 | Medical adhesives |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US23513899A | 1999-01-22 | 1999-01-22 | |
US09/235,138 | 1999-01-22 |
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WO2000043050A1 true WO2000043050A1 (en) | 2000-07-27 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/US2000/001215 WO2000043050A1 (en) | 1999-01-22 | 2000-01-19 | Medical adhesives |
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Country | Link |
---|---|
EP (1) | EP1146917A1 (en) |
JP (1) | JP2002535046A (en) |
CN (1) | CN1341032A (en) |
AU (1) | AU2730600A (en) |
BR (1) | BR0007644A (en) |
CA (1) | CA2358565A1 (en) |
WO (1) | WO2000043050A1 (en) |
ZA (1) | ZA200105842B (en) |
Cited By (23)
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WO2001082992A1 (en) * | 2000-04-28 | 2001-11-08 | Emory University | Decellularized vascular prostheses |
EP1335690A2 (en) * | 2000-09-29 | 2003-08-20 | Praxis LLC | In-situ bonds |
DE10242075A1 (en) * | 2002-09-11 | 2004-03-25 | Curasan Ag | New bone-adhesive polyurethane polymers obtained using polyester polyol component(s), having high tensile strength and useful e.g. for fixing bone or tooth fragments or filling cavities |
WO2009117737A3 (en) * | 2008-03-21 | 2010-11-04 | Biomimedica, Inc | Methods, devices and compositions for adhering hydrated polymer implants to bone |
US7858078B2 (en) | 2005-12-06 | 2010-12-28 | Tyco Healthcare Group Lp | Bioabsorbable surgical composition |
US7910129B2 (en) | 2005-12-06 | 2011-03-22 | Tyco Healthcare Group Lp | Carbodiimide crosslinking of functionalized polyethylene glycols |
US7947263B2 (en) | 2005-12-06 | 2011-05-24 | Tyco Healthcare Group Lp | Biocompatible surgical compositions |
US7998466B2 (en) | 2005-12-06 | 2011-08-16 | Tyco Healthcare Group Lp | Biocompatible tissue sealants and adhesives |
US8044234B2 (en) | 2005-05-05 | 2011-10-25 | Tyco Healthcare Group Lp | Bioabsorbable surgical composition |
US8288477B2 (en) | 2005-12-06 | 2012-10-16 | Tyco Healthcare Group Lp | Bioabsorbable compounds and compositions containing them |
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US6689161B2 (en) | 2000-04-28 | 2004-02-10 | Baylor College Of Medicine | Decellularized vascular prostheses resistant to thrombus occlusion and immunologic rejection |
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EP1335690A2 (en) * | 2000-09-29 | 2003-08-20 | Praxis LLC | In-situ bonds |
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DE10242075A1 (en) * | 2002-09-11 | 2004-03-25 | Curasan Ag | New bone-adhesive polyurethane polymers obtained using polyester polyol component(s), having high tensile strength and useful e.g. for fixing bone or tooth fragments or filling cavities |
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Also Published As
Publication number | Publication date |
---|---|
JP2002535046A (en) | 2002-10-22 |
CN1341032A (en) | 2002-03-20 |
CA2358565A1 (en) | 2000-07-27 |
AU2730600A (en) | 2000-08-07 |
EP1146917A1 (en) | 2001-10-24 |
BR0007644A (en) | 2002-01-08 |
ZA200105842B (en) | 2002-10-16 |
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