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BIOCOMPATIBLE ADHESION IN TISSUE REPAIR
This application is a continuation of application Ser. No. 08/668,595 filed Jun. 18, 1996, noW abandoned, Which is a continuation of application Ser. No. 08/408,013, filed Mar. 21, 1995, noW abandoned.
BRIEF DESCRIPTION OF THE INVENTION
The invention relates to a process for aiding tissue repair in non-dental treatment of a mammal that involves the (a) healing process of injured soft tissue, and (ii) damaged osseous material, and (b) for enhancing the biocompatibility and adhesion of bone and/or prosthetic device (typically made of metal, ceramic or plastic) involved in a surgical or nonsurgical repair procedure, to ossified and non-ossified tissue components With Which they are in contact. The invention involves treating the injured non-dental related soft tissue, osseous material, bone and/or prosthetic device With a special biocompatible crosslinked resin that optionally contains leachable fluoride.
BACKGROUND OF THE INVENTION
Dentistry is the science concerned With the diagnosis, prevention, and treatment of diseases of the teeth, gums, and related structures of the mouth and includes the repair or replacement of defective teeth. Dental (i.e., relating to, or for the teeth) treatments involve those compositions, articles and processes encompassed Within the field of dentistry. The terms “non-dental applications and treatments” and “nondental-related”, as used herein and in the claims hereof, address activities exclusive of activities that are part of the field of dentistry. GeristoreTM and TenureTM, sold by Den-Mat Corporation, Santa Maria, Calif., are promoted for certain uses in dentistry. U.S. Pat. Nos. 4,738,722, 5,334,625 and 5,151,453, incorporated herein by reference, describe GeristoreTM. GeristoreTM is a small particle composite that contains fluoride, is radiopaque and hydrophilic. It has loW-cure shrinkage, loW coefficient of thermal expansion and high strength. It aggressively bonds by chemical coupling to dentin, enamel, composites used in dentistry, porcelain and metal, such as stainless steel. It is a paste/paste formulation that is easy to mix. It is capable of rapid cure by exposure to room temperature and for more rapid cure, by exposure to light. In addition, though it contains a fluoride, Which could be toxic When ingested in large dosages, it is biocompatible and safe to use Within a human or other animal When applied topically. TenureTM is a solvent based crosslinkable acrylic resin, provided as a solution/solution formulation. Its composition is described in U.S. Pat. No. 4,964,911, patented Oct. 27, 1990, and more effectively disclosed in alloWed copending application Ser. No. 965,102, filed Oct. 22, 1992, to issue as U.S. Pat. Re 34,937, the disclosure of Which is incorporated by reference. It is not an ionomer and does not release fluoride ion. It is less hydrophilic than GeristoreTM. It too is a crosslinkable resin. It contains a volatile solvent (typically acetone), Which readily evaporates. After evaporation, a film of the resin rapidly cures in situ. TenureTM bonds by chemical coupling to dentin, enamel, porcelain, metal and the composites typically used in dentistry. It has been recommended for use With GeristoreTM in chemically bonding GeristoreTM to dentin or enamel. Galan, Journal Of Esthetic Dentistrv, Vol. 3, No. 6, (Nov./Dec. 1991), describes the general use of GeristoreTM
in the restoration of teeth and lesions both supra and subgingivally located.
M. Dragoo (unpublished) has used GeristoreTM in subgingival restorations of teeth to treat subgingival root resorption, split roots, endo perforation, tooth fracture, external root resorption and root coverage over previously restored and/or eroded root surfaces. He found the GeristoreTM aided in rebuilding biologic Width, resulting in neW tissue attachment, and minimized plaque induced gingivitis.
There is much art on the use of hydroxyethylmethacrylate (“HEMA”) to make hygroscopic polymers such as a homopolymer of HEMA (“PHEMA”). Such HEMA based polymers typically form Water sWellable hydrogels. HEMA contains the sym. (or 1,2-) ethylene bis-methacrylate (ethylene glycol dimethacrylate) as a byproduct. This byproduct crosslinks the HEMA based polymers to alloW formation of useful hydrogels. One such hydrogel form is used to make soft contact lens by cast molding HEMA containing small amounts of ethylene bis-methacrylate. One advantage of PHEMA based systems that alloWs use in physiological applications is the biocompatibility of the polymer. HoWever, their use as described in the patent literature has been limited merely to transporting drugs and other materials to a bodily function based on their absorptive qualities or as an inert interface about a device to render that device biocompatible. See for example, U.S. Pat. No. 3,566, 874, Which describes the encapsulation of a catheter With a casting syrup of HEMA. The hydrogel form of the polymer of HEMA (“PHEMA”) is renoWned for its capacity to absorb moisture to generate a sWollen film. Some patents describe PHEMAproducts into Which other ingredients have been absorbed. In this respect, the PHEMA product, as such, is merely a reservoir for that ingredient. U.S. Pat. No. 3,566,874 describes the inclusion in a HEMA casting syrup of a germicide or an antibiotic. U.S. Pat. No. 4,303,066, makes a burn dressing by dispensing separate phases of a PHEMA and a high boiling liquid on a burn to serve as a dressing. As a consequence, the absorptive characteristic of PHEMA is being used only for the high boiling liquid Which is provided supposedly for heat transfer purposes. U.S. Pat. No. 3,674,901 describes the coating of a HEMA based solvent solution to coat surgical suture threads. The patent includes antibiotics, antiseptics or bactericides absorbed into the cured resin. In this case, hoWever, the resin is foamed first before the adsorption takes place. In U.S. Pat. No. 3,849,185, a HEMA coumarone-indene type resin casting material is mixed With materials such as heparin and used as a coating material. On the other hand, U.S. Pat. No. 3,868, 447 describes a highly filled solvent-based HEMA paste to Which biologically active ingredients can be added. The paste has been described for use in dental applications, such as a cover for dental fillings, or as a carrier for NovocainTM in dental surgery. Though HEMA and PHEMA contain hydroxyl groups and hydroxyl groups are thought to aid in adhesion, the adhesion of such groups to a physiologically active surface is materially and adversely affected by the presence of Water at the surface. Consequently, bonding of HEMA to a physiologically involved surface Which contains moisture at its surface requires some ingredient in the resin that aids in bonding to such a surface.
Non-dental related body tissues are oftentimes subjected to undesirable afflictions such as irritation, decay or damage of bone or soft tissue. Irritation can be reflected in
inflammation, decay can involve erosion and/or decomposition of tissue, and damage can be a wound or fracture. This invention involves topically treating mammalian, preferably human and domestic animal, non-dental-related, afflicted tissue with certain coating materials to decrease the impact 5 of such afflictions.
More particularly, the invention relates to a process for enhancing the
(a) normal healing process of
(i) injured non-dental-related soft tissue, and 10
(ii) non-dental-related osseous material, and
(b) for enhancing the biocompatibility and adhesion of bone and/or prosthetic device (typically made of metal, ceramic or plastic) involved in a non-dental surgical or nonsurgical repair procedure, to ossified and nonossified tissue components with which they are in contact.
The invention relates to processes to enhance non-dentalrelated physiological functioning of a live mammalian body, 2Q preferably a live human or domesticated animal body, where there is an injury to either soft or hard tissue or a nonbiocompatible prosthesis is placed in the body, that involves placing at the injury or on the prosthesis
a) a tenaciously-bonded hydrophilic water insoluble 25 crosslinked resin coating (hereinafter called "the primary coating")
b) that optionally contains a measurable amount of a water/fluid leachable fluoride capable of (a) being leached from the coating in a metered amount, and (b) 30 transporting a small amount of leached fluoride from the coating into the afflicted area (hereinafter called "the primary coating with fluoride").
In one aspect, the invention encompasses a process for enhancing the normal healing processes of a non-dental 35 related wound, and the biocompatibility and adhesion of non-dental-related bone and/or prosthetic device (typically made of metal, ceramic or plastic) involved in a non-dentalrelated surgical and/or wound repair procedure, to body cellular (e.g., tissue) components with which they are in 40 contact. This is accomplished by providing during such procedure, at the area of a wound, a surface containing the primary coating or the primary coating with fluoride. The amount of fluoride provided in the primary coating is insufficient to cause fluorosis or any other toxic reaction, 45 and, by processes unknown, except possibly antimicrobial processes, the fluoride assists the normal processes of wound healing. The invention also relates to a process for joining bone and/or prosthetic device surfaces in non-dentalrelated surgical procedure, by applying the primary coating 50 or the primary coating with fluoride, to tenaciously bond to one or more of the surfaces prior to completion of the surgical repair.
The invention also encompasses in these non-dentalrelated processes, the use of a composite layering of a 55 strongly adhesively-bonded crosslinkable acrylic resin, possessing less hydrophilicity than the primary coating with or without fluoride, that rapidly in situ cures on an application surface, the bone and/or prosthetic surface, to function as a primer (hereinafter called the "primer coating") for the 60 primary coating with or without fluoride that is applied to the same surface(s). The biocompatibility of the primary coating on the surface, bone and/or prosthetic device over the primer coating enhances healing, the adhesion of the bone to bone and bone to softer tissue, and prosthetic device to bone or 65 softer tissue, and precludes or minimizes bone or softer tissue rejection to the surgical procedure.
More particularly, the invention relates to a non-dentalrelated topical wound treatment that involves the application over a wound of a film or layer of the primary coating with or without fluoride. The primary coating with or without fluoride may be cured as a thin film on a non-adhesive surface such as glass or Teflon® and as a released film may be put in contact with the wound. The primary coating with or without fluoride may be coated on an adhesive receptive surface (such as plastic or cloth) and cured, and then applied to the wound in the manner of a wound dressing. The primary coating is stable on contact with the wound, and promotes healing of the wound. This allows fluid contact with the optionally provided fluoride component within the coating and, by virtue of the releasibility of the fluoride by leaching, fluoride is metered from the coating and into the wound area. Because of the nature of the source of fluoride, it is possible to control the leaching rate of fluoride and obtain a predetermined metered amount of fluoride transported from the coating into the wound area.
Also, the invention relates to a process for enhancing the biocompatibility and adhesion of bone and/or prosthetic device (typically made of metal, ceramic or plastic) during a non-dental-related surgical procedure, to soft tissue with which they are in contact. This is accomplished by joining non-dentalrelated bone and/or prosthetic device surfaces after applying the primary coating with or without fluoride to one or more of the surfaces prior to completion of the repair. It is also desirable to utilize a composite layering of the primer coating and the primary coating with or without fluoride. In this embodiment, the primer coating rapidly in situ cures (e.g., cold cures or autopolymerizes) on the bone and/or prosthetic surface before primary coating is applied to that same surface(s). The biocompatibility of the primer coating on the bone and/or prosthetic device enhances the adhesion of the bone to bone and bone to tissue, and prosthetic device to bone or tissue, while at the same time averting or minimizing bone or tissue rejection to the surgical procedure.
This invention is directed to a novel non-dental-related process in which primary coating with or without fluoride alone, or in combination with the primer coating, is topically applied to non-dental-related bone, prosthesis and soft tissue to enhance the biocompatibility and adhesion of bones and/or prosthetic devices involved in body repair. The enhancement of biocompatibility is believed to occur due to the inherent biological compatibility of the coating, its safe and substantial bonding to bone or a medical device implanted in the body, and, when present, through the metered release of small and safe quantities of fluoride to thereby aid the healing process. It is believed that the fluoride provides in the wound safe antimicrobial properties, thereby advancing the healing process.
In a further particular embodiment of the invention, in a non-dentalrelated surgical procedure involving bone repair within a body, such as a bone fracture, which involves the process of incising skin to expose an area in which bone undergoing restoration resides, exposing the bone undergoing repair, defining within the exposed area the manner of restoration of the bone, preparing the area for said restoration, effecting the restoration, and closing the area after completion of the surgical procedure by closing the skin over the area and providing for the natural or aided healing of any wound associated with such procedure, the improvement which comprises, during said restoration, the step of selecting at least one bone surface within the exposed area that is to be bonded, coating that surface with the primary coating with or without fluoride, alone or in
combination, such as in sequence, With the primer coating, contacting the coated surface With bone or a prosthetic device, curing the coating by exposing the coating to light or to ambient temperature. In still another particular embodiment of the invention, in a non-dentalrelated surgical procedure to implant a prosthetic device Within a body Which involves the process of incising skin to expose an area of the body in Which the prosthetic device is to be inserted, defining Within the exposed area the manner of restoration therein by implantation of the prosthetic device, preparing the area for said restoration, effecting the restoration, and closing the area after completion of the surgical procedure by closing the skin over the area and providing for the natural or aided healing of any Wound associated With such procedure, the improvement Which comprises, during said restoration, the step of selecting at least one prosthetic device surface Within the exposed area that is to be bonded, coating that surface With the primary coating With or Without fluoride alone, or in combination, such as in sequence, With the primer coating, contacting the coated surface With bone and/or tissue, or including the step of adding a patch of cured film of the primary coating With fluoride, curing the coating by exposing the coating to light or to ambient temperature. In an another embodiment of the invention, there is described a nondental-related process for aiding in the healing of an open Wound or an exposed Wound (such as a subcutaneous, penetrating (including a traumatopneic Wound), perforating, or tangential Wound) Which comprises superimposing a cured layer of primary coating With fluoride onto the Wound such that the tissues at the Wound surface are in direct contact With the layer, and maintaining such a layer in contact With the Wound at least until such time as the Wound is closed as a result of the healing process. In this treatment, it is desirable to form a thin cured layer of primary coating With fluoride, coat one surface of the cured layer With uncured primary coating With fluoride, and cure the coating While it and the cured layer are in contact With the Wound by exposing the uncured coating to light or to ambient temperature. In still another embodiment of the invention, there is described a nondental-related process for repairing an injured or degenerated osseous material Which comprises superimposing a patch of cured layer of the primer coating With fluoride onto the injured or degenerated area of the osseous material, leaving such patch in contact With the area and alloWing groWth of the osseous material to encompass the patch and repair the injured or degenerated area. In this treatment, it is desirable to form a thin layer primary coating With fluoride, and coat one surface of the cured layer With uncured primary coating With fluoride, and cure the primary coating While it and the cured layer is in contact With the area undergoing treatment by exposing the coating to light or to ambient temperature. The primary coating comprises a resin based on an ethylenically unsaturated-functional monomer that contains a hygroscopic group. The ethylenically-unsaturatedfunctional monomer contains hygroscopic groups and exhibits hydrophilicity. Typical of such groups are hydroxyl, amide, amine, aliphatic ether, amine, hydroxyalkyl amine, hydroxyalkyl amide, pyrrolidone, ureyl, and the like. Another ingredient of the primary coating composition is a polycarboxylic acid, i.e., a polymer that contains pendant carboxyl groups. The polycarboxylic acid is thought to enhance bonding of the primary coating resins to metallic and other substrates, particularly to organic and inorganic salt forming materials that are present in the substrate to
Which the primary coating is applied. In addition, the polycarboxylic acid enhances the bonding of the resin components of the primary coating composition to any inorganic fillers provided in the coating formulation. In a number of contemplated uses for the primary coating, in accordance With this invention, the polycarboxylic acid may be excluded from the primary coating formulation. In addition, one may employ the alkali metal salt of the polycarboxylic acid. In addition, the primary coating contains a variety of crosslinking agents. One type of crosslinking agent is “hard crosslinker” and another is a “soft crosslinker.” Both hard and soft crosslinker are polyfunctional molecules in Which the functionality is complementary to the ethylenic unsaturation of the ethylenically-unsaturated-functional monomer. In the case of the hard crosslinker, the functional groups are bonded via an aliphatic group of up to carbon atoms, to a central moiety that is aromatic in nature, that is, comprises a group that has the rigidity characteristics of a benzene ring. Illustrative of such rigid groups are aromatic rings such as benzene, biphenyl, anthracyl, benzophenone, norbornyl, and the like. Such hard crosslinkers raise the Tg of the cured coating. The soft crosslinker contains the functional groups bonded to a central moiety that is aliphatic in nature, that is, comprises a group that has the flexibility of an alkane or an alkyl benzene containing. Illustrative of such flexible groups are the residues of ethylene glycol, diethylene glycol, 2,2bis(4-hydroxyphenyl)propane, 2,2,-bis(4-hydroxyphenyl) fluorinated alkanes, and the like. Such soft crosslinkers toughen the cured coating and can raise the Tg of the cured coating, but not as high as the typical hard crosslinker. Another feature of the primary coating is that it tenaciously bonds to surfaces onto Which it is coated as Well as securely tie up any inorganic filler that is included in the primary coating formulation. In order to achieve this, the coating contains a coupling agent as part of its formulation. These coupling agents provide chemical bonding to the surface to Which the coating is applied. Chemical bonding means strong and Weak bonding forces. Strong bonding forces, as used herein, refers to covalent, ionic, hydrogen bonding and complexation, and Weak bonding forces, encompasses the other forms of bonding. Where Weak bonding forces are employed, the extent of such bonding is such that the adhesion to the surface is of the nature of a stronger bonding force. For example, van der Waal forces are Weak bonding forces. In the case of the invention, the amount of such forces existing betWeen the coating and the surface Will be sufficient to give the performance of a stronger bonding force. A desirable coupling agent is a material, such as a molecule, that is functionally complementary to the ethylenically-unsaturated-functional monomer. Desirably, the coupling agent contains a functional group that is reactable With the ethylenic unsaturation. Preferably, the functional group is an acrylic-type ethylenic unsaturation. At another part of the coupling agent molecule is a surface bonding group that can impart one or more properties to the primary coating: 1) chemical bonding capabilities to the substrate surface to Which the primary coating is applied; and/or 2) Wetting agent properties in that it reduces the surface tension of the coating, causing the coating to spread across or penetrate more easily the surface of the substrate onto Which the primary coating is applied. The utilization the primary coating With fluoride is a special and significant embodiment of the invention. The
fluoride component optionally provided in the primary coating is desirably present in the coating such that it is leachable from the coating over an extended period of time.
In order to cure the primary coating, the primary coating formulation is provided with a conventional free-radical 5 catalytic curing agent and/or a freeradical photoinitiator. When both are provided, the coating can be cured by each of the system, preferably by both to insure that volatile monomeric components are left as residual components in the coating. This avoids the possibility of toxic reaction to 10 the presence of such volatile monomeric components.
In respect to the above processes, the invention relates to the improvement where the primary coating comprises a two component system of:
(a) a first component comprising: j5
(1) the fluoride source, such as a particulate siliceous
fluoride containing filler in which the fluoride is
(2) a coupling agent, such as one or more of (i)
N-phenylglycine, the alkali metal salt thereof, or the 2o
mixture of the foregoing two compounds, (ii) the
adduct of N-(p-tolyl)glycine and glycidyl
methacrylate, the alkali metal salt thereof, or the
mixture of the foregoing two compounds, and (iii)
the adduct of N-phenylglycine and glycidyl 25
methacrylate, the alkali metal salt thereof, or the
mixture of the foregoing two compounds;
(3) a photoinitiator; if desired, a radiopaquing agent;
and, if desired, a buffering agent; and
(b) a second component comprising: 30
(1) the ethylenically-unsaturated-functional monomer;
(2) a soft crosslinker such as 2,2-bis(4-methacryloxy
2-ethoxy phenyl)propane, diethyleneglycol bis
methacrylate, and the like;
(3) a hard crosslinker such as one or more of (i) the 35
adduct of pyromellitic acid dianhydride and
2-hydroxyethyl methacrylate, (ii) the adduct of 3,3',
4,4'-benzophenonetetracarboxylic dianhydride and
4-methacryloxyethyltrimellitic anhydride, and (iv) 40
other compounds containing at least one group or
moiety capable of free radical polymerization and at
least one aromatic ring or moiety containing
electron-withdrawing substituents that do not inter-
fere with free radical polymerization; 45
(4) a photoinitiator;
(5) a polymerized carboxylic acid;
(6) a free-radical scavenger; and
(7) a curing catalyst.
In another embodiment of the primary coating, it may be 50 a light-curable adhesive composition of the following twocomponent system:
(a) a first component comprising:
(1) a fluoride source such as a particulate siliceous fluoride containing filler in which the fluoride is 55 water leachable;
(2) a soft crosslinker;
(3) an ethylenically-unsaturated-functional monomer;
(4) a photoinitiator;
(5) a free-radical scavenger; 60
(6) a thermal initiator;
7) a polymerized carboxylic acid;
(8) a hard crosslinker such as one or more of (i) the adduct of pyromellitic acid dianhydride and 2-hydroxyethyl methacrylate; (ii) the adduct of 3,3', 65 4,4'-benzophenonetetracarboxylic dianhydride and 2-hydroxyethylmethacrylate, (iii)
4-methacryloxyethyltrimellitic anhydride, and (iv) other compounds containing at least one group or moiety capable of free radical polymerization and at least one aromatic ring or moiety containing electron-withdrawing substituents that do not interfere with free radical polymerization, and (b) a second component comprising:
(1) a fluoride source such as a particulate siliceous fluoride containing filler in which the fluoride is water leachable;
(2) a soft crosslinker;
(3) an ethylenically-unsaturated-functional monomer;
(4) a coupling agent such as one or more of (i) N-phenylglycine, the alkali metal salt thereof, or the mixture of the foregoing two compounds, (ii) the adduct of N-(p-tolyl)glycine and glycidyl methacrylate, the alkali metal salt thereof, or the mixture of the foregoing two compounds, and (iii) the adduct of N-phenylglycine and glycidyl methacrylate, the alkali metal salt thereof, or the mixture of the foregoing two compounds;
(5) a photoinitiator; if desired, a radiopaquing agent; and, if desired, a buffering agent.
A more specific embodiment of the primary coating composition is the following composition:
1. A particulate glass having the composition set forth in Table 1 below;
2. A coupling agent:
The alkali metal salt of the adduct of N-(p-tolyl)glycine and glycidyl methacrylate; e.g.,
1. A hard crosslinker: The adduct of pyromellitic acid dianhydride and 2-hydroxyethyl methacrylate;
2. A photoinitiator: Ethyl 4-dimethylamino benzoate and camphoquinone (i.e., 2,3-bornanedione);
3. A soft crosslinker: Ethoxylated bisphenol A dimethacrylate and the adduct of glycidylmefhacrylate and bisphenol A,
4. An ethylenically-unsaturated-functional monomer:
2- hydroxyethyl methacrylate;
5. Butylated hydroxytoluene free radical scavenger.
6. A poly carboxylic acid;
7. Benzoyl peroxide or other peroxides that cause free radical addition at about 55° C. or at a lower temperature.
The primer coating involves a two part (package) composition, comprising
(a) a compound selected from the group consisting of (1) N-phenylglycine, (2) the adduct of N-(p-tolyl) glycine and glycidyl methacrylate, (3) the addition reaction product of N-phenylglycine and glycidyl methacrylate, (4) N(p-tolyl) glycine, N-phenylalanine, sarkosine, N-lauroylsarkosine, glycine, N,N-dimefhyl-glycine,
3- (N-phenyl) amino propionic acid, 3-(N-ptolyl) amino propionic acid, omega-amino fatty acids, N-substitutedomega-amino fatty acids, and the other