In situ bulking device

The present invention relates to a hydrated, biocompatible tissue-augmentation compound and its methodology for implantation into mammalian tissue. The tissue-augmentation compound is comprised of: living tissue, body derived fluids, at least one NCO-terminated hydrophilic urethane prepolymer derived from an organic polyisocyanate, and oxyethylene-based diols or polyols comprised essentially all of hydroxyl groups capped with polyisocyanate

BACKGROUND OF THE INVENTION
 1. Field of the invention
 The invention relates to methods and substances comprising a biocompatible,
 non-degradable polymer of stable volume for the purpose of augmenting
 mammalian tissue.
 2. Prior Art
 This invention relates to synthetic surgical adhesives/sealants and tissue
 bulking created by reacting the adhesive tissue augmentation injectable
 with living in situ tissue. More specifically, a unique tissue
 cross-linked polyurea-urethane bond formed by reaction of isocyanate
 capped ethylene oxide diols, triols or polyols with living tissue forms an
 immobilized, non-biodegradable augmentation of tissue.
 Numerous bulking and plastic surgery applications have been published, but
 none of them teach bulking by means of the novel substance disclosed here
 and further none of them provide adhesion to tissue. Thus in these prior
 arts, there is susceptibility to implant migration. The present invention
 is biocompatible. Prior art bulking substances are also known to be
 biocompatible, but they are also biodegradable. Biodegradability of an
 implant in a tissue augmentation procedure is generally not desirable
 since the benefits conferred by the implanted substance disappear with
 time.
 U.S. Pat. No. 5,785,642 (Wallace et al.) describes a 3-part injectable
 polymer for treating incontinence. While the patent claims improved
 resistance to migration, principally when compared with particulate
 injectables, it does not describe a tissue bond to guard against implant
 migration. Furthermore, the disclosed invention involves forming a polymer
 precipitate in situ from a solvent/polymer system. Since the solvent does
 not entirely become part of the precipitate, then some of the injected
 solvent volume is eventually lost to absorption into the surrounding
 tissue. Thus, the invention does not teach a device which has a stable
 volume once implanted.
 U.S. Pat. No. 5,712,252 (Smith) describes a method of augmenting soft
 tissue in a mammal, which includes injecting keratin into soft tissue.
 Keratin is a biodegradable substance.
 U.S. Pat. No. 5,763,399 (Lee) describes a composition and method for
 effective revitalization of scar tissue by injecting a bioactive substance
 having angiogenic activity. The revitalization of scar tissue is intended
 to augment existing tissue. However, this invention cannot control the
 extent of augmentation.
 U.S. Pat. No. 5,922,025 (Hubbard) describes a permanent, biocompatible
 material for soft tissue augmentation. The biocompatible material
 comprises a matrix of smooth, round, finely divided, substantially
 spherical particles of a biocompatible ceramic material. However,
 prevention of migration of the ceramic material is not described.
 U.S. Pat. No. 5,976,526 (Atala) describes treatment of vesicoureteral
 reflux, incontinence and other defects using an injectable of bladder
 cells mixed with a liquid polymeric material. This material is susceptible
 to biodegradation.
 U.S. Pat. No. 5,855,615 (Bley at al) describes a composition for injecting
 into the urethra comprising a plurality of physiologically acceptable
 solid polymer particles dispersed in a physiologically acceptable
 biodissipatable liquid carrier. The solid polymer particles are capable of
 hydrating to a predetermined volume. The injection volume is therefore not
 necessarily the same as the final hydrated volume.
 U.S. Patent No. 5,709,854 (Griffith-Cima et al) describes a cell polymeric
 solution that self-cross-links, but does not bond to tissue, for the
 purpose of inducing tissue formation.
 One of the primary uses of the present invention is treatment or urinary
 incontinence. In particular, many women suffer from incontinence caused by
 childbirth or obesity. The initial treatment for stress incontinence is
 exercise to strengthen the pelvic floor muscles. If these exercises are
 ineffective, open surgical repair of the bladder neck is often attempted.
 Such surgical repair procedures are not successful for all patients. There
 is also risk associated with open surgical procedures, such as trauma,
 infection, and risks of anesthesia.
 As an alternative to surgical repair, urinary incontinence has been treated
 by injecting various substances into the tissue surrounding the urethra,
 i.e., the periurethral tissue, to add bulk to this tissue. The aim of this
 treatment is to compress the urethra at the level of the bladder neck to
 impede involuntary flow of urine from the bladder.
 Murless has reported the use of sodium morrhuate for the treatment of
 stress incontinence (J. Obstet. Gynaecol., 45:67-71(1938)). This material
 was not successful in treating incontinence and pulmonary infarction was
 an observed complication. Paraffin (Acta Urol. Belg., 23:259-262(1955))
 and other sclerosing solutions (Urol. Int., 15:225-244(1963)) have been
 tried yielding poor results.
 Polytetrafluoroethylene particles (TEFLON.TM., POLYTEF.TM.) have been used
 as injectable bulking material with a success rate from 30% to 86% in some
 studies (J. Urol.,111:180-183(1974); Br.J.Urol.,55:208-210(1983)
 210(1983); BMJ 228;192 (1984); J .Urol.,(Paris), 62:39-41(1987);
 Br.J.Urol., 62:39-41 (1988); Aust. N.Z.J.Surg., 61:663-666 (1966)). The
 complications associated with this procedure were foreign body granulomas
 that tended to migrate to distant organs, such as the lungs, liver, spleen
 and brain (JAMA, 251:3227-3281 (1984)).
 Another injectable used recently is glutaraldehyde cross-linked bovine
 dermal collagen (Med. J. Aust., 158:89-91 (1993); Br. J. Urol., 75:359-363
 (1995); Br.J.Urol., 75: 538-542 (1993)). A major problem with the use of
 collagen was biodegradation with associated decrease in implant volume
 over time necessitating retreatment (J.Urol., 150:745-747 (1993)).
 Collagen can also cause adverse immune responses and allergic reactions to
 bovine collagen have been described (Br.J.Urol., 75:359-363 (1995)).
 Other materials have been suggested for use in the treatment of
 vesicourectal reflux. These substances include polyvinyl alcohol foam (J
 .Urol., 144:531-533 (1990)), glass particles (J.Urol., 148:645 (1992)), a
 chondrocyte-alginate suspension (J.Urol., 150:745-747 (1993)) and a
 detachable silicone balloon (J.Urol., 148:724-728 (1992)), each of these
 cited journals being incorporated herein by reference.
 Injectables have not been suggested for treatment of gastroesophageal
 reflux disease (GERD), but such use of the disclosed material of this
 application is envisioned. The material may be injected into the wall of
 the esophagus to thicken the wall and narrow the gastroesophageal junction
 into the stomach.
 In addition to the need for an immobilized, volume-constant, biocompatible
 implant, there is also a need to be able to visualize the volume of
 injected material during and after implantation. It would be preferred to
 monitor the implant size by non-invasive means. Furthermore, fluoroscopic
 imaging of the implant would aid in estimation of the implant size and
 location if follow-up injections are necessary.
 In addition, polymerization time of the injected material is an important
 parameter since the material is typically delivered as a low viscosity
 solution that may leak from the site after needle removal. The lower the
 viscosity of the injectable the smaller the needle that may be used.
 Finally, there are several pragmatic considerations. For example, the
 injectable material should not polymerize in the needle of the delivery
 device so as to necessitate replacement of the needle during the
 procedure. The solution should be of low viscosity to enable easy delivery
 of the solution through a 23 G needle.
 BRIEF SUMMARY OF THE INVENTION
 This invention is directed toward all applications where bulking of tissue
 provides a functional or aesthetic result. Accordingly, in one of its
 method aspects, this invention is directed to a method for treating
 urinary incontinence in a mammal, which method comprises delivery of a
 single composition comprising a biocompatible prepolymer and a contrast
 agent to the periurethral tissue of a mammal.
 It is an object of the present invention to provide a bulking mass that
 chemically bonds in situ to living tissue that is biocompatible,
 elastomeric, and non-biodegradable.
 It is another object of this invention to provide an adhesive formulation
 for tissue augmentation surgery having short bonding and polymerization
 time.
 It is another object of this invention to provide an adhesive bulking
 material which is non-toxic and non-immunogenic.
 It is another object of this invention to provide a low viscosity adhesive
 bulking material permitting delivery through a 23 G needle.
 It is another object of this invention to provide a bulking material that
 does not undergo appreciable volume change acutely during polymerization
 or chronically after implantation in tissue.
 It is another object of this invention that the bulking material provide
 fluoroscopic contrast for noninvasive visualization during and after
 implantation.
 It is another object of this invention that the prepolymer composition be
 gamma sterilizable without appreciable cross-linking of the prepolymer or
 altering its hydrated tissue bond functionality.
 The tissue augmentation of this invention is achieved by reacting the
 target tissue with a solution of a high molecular weight ethylene oxide
 polyol, triol or diol end-capped with an organic polyisocyanate.
 The tissue augmenting agent of this invention may alternatively be a
 polyisocyanate capped copolymer of ethylene oxide and polypropylene.
 The tissue augmenting agent of this invention may additionally contain, in
 solution, viscosity lowering inert components such as Perfluronbon or
 physiologic saline.
 It is one primary object of this invention to provide a tissue augmentation
 solution that is easily applied, cures quickly in situ, and produces a
 strong tissue bond. The preparations disclosed here can be stored at
 normal hospital room temperatures, and possess long shelf life.
 The invention thus comprises a hydrated, biocompatible tissue-augmentation
 compound comprised of: living tissue, body derived fluids, at least one
 NCO-terminated hydrophilic urethane prepolymer derived from an organic
 polyisocyanate, and oxyethylene-based diols or polyols comprised
 essentially all of hydroxyl groups capped with polyisocyanate. The
 prepolymer units may preferably be aliphatic or aromatic isocyanate-capped
 oxyethylene-based diols or polyols. The molecular weight of the diols or
 polyols prior to capping with polyisocyanate is prefarably at least 3,000.
 The polyisocyanate may be a Toluene diisocyanate. The polyisocyanate may
 be isophorone diisocyanate. The polyisocyanate may be a mixture of Toluene
 diisocyanate and 6-chloro 2,4,5-trifluoro1,3 phenylene diisocyanate. The
 polyisocyanate may be a mixture of Toluene diisocyanate and
 tetrafluoro1,3-phenylene diisocyanate. The polyisocyanate may be a mixture
 of diphenylmethane diisocyanate and 6-chloro 2,4,5-trifluoro1,3 phenylene
 diisocyanate. The polyisocyanate may be a mixture of diphenylmethane
 diisocyanate and tetrafluoro-1,3-phenylene diisocyanate. The
 polyisocyanate may be para-phenylene diisocyanate. The diols or polyols
 may be capped with polyisocyanate wherein the isocyanate-to-hydroxyl group
 ratio is between 1.5 and 2.5. The isocyanate concentration in the
 prepolymer units may be between 0.05 and 0.8 milliequivalents per gram.
 The hydrated, biocompatible tissue-augmentation compound may further
 comprise a biocompatible solvent comprised of acetone to control viscosity
 and cure time. The hydrated, biocompatible tissue-augmentation compound
 may further comprise a contrast agent comprised of meglumine. The
 hydrated, biocompatible tissue-augmentation may further be comprised of a
 low molecular weight uncapped polyethylene glycol, consisting of PEG 300
 as a solvent. The hydrated, biocompatible tissue-augmentation compound may
 be further comprised of a contrast agent and a biocompatible solvent in
 combination. The hydrated, biocompatible tissue-augmentation compound may
 be further comprised of physiological saline. The hydrated, biocompatible
 tissue-augmentation compound may be comprised of between 10-30%
 physiologic saline. The hydrated, biocompatible tissue-augmentation
 compound may be comprised of 10-20% physiologic saline. The hydrated,
 biocompatible tissue-augmentation compound of may include an injectable
 material selected from the group comprised of: collagen, silicone, teflon,
 or pyrolytic carbon coated beads.
 The invention also includes a method of preparing a crosslinked
 hydrophilic, biocompatible hydrated tissue-augmentation compound by
 reacting together mammalian body tissue, body derived fluids and a
 prepolymer in a prepolymer-to-water ratio of 3:1 to 20:1, the prepolymer
 prepared by the steps of: selecting diols or polyols from
 oxyethylene-based diols or polyols having an average molecular weight of
 3,000 to about 30,000, and reacting the diols or polyols with an aliphatic
 or aromatic polyisocyanate at an isocyanate-to-hydroxyl ratio of about 1.5
 to 2.5 so that all of the hydroyl groups of said diols or polyols are
 capped with polyisocyanate and the resulting prepolymer has an isocyanate
 concentration of no more than 0.8 milliequivalents per gram. The diols or
 polyols may be oxyethylene-based diols or polyols. The diols and polyols
 of step (a) may be dissolved in an organic solvent selected from the group
 comprising acetonitrile or acetone. The hydrated tissue-augmentation
 compound may include a solution of non-body derived water, including a
 saline solution containing 0.9% NaCl. The prepolymer-to-water ratio may be
 between 3:1 to 20:1. The method may include the step of: washing the bond
 with a polyfunctional diamine to end isocyanate reactivity.
 The invention also includes a prepolymer solution for preparing a
 hydrophilic, biocompatible tissue augmentation compound characterized by
 volume conservation, and resistance to decomposition within the body, said
 prepolymer consisting of: oxyethylene-based diols or polyols having an
 average molecular weight in excess of 3,000, the diols or polyols having
 all of the hydroxyl groups capped with an aromatic or aliphatic
 diisocyanate; and an adhesive tissue augmentation injectable having an
 isocyanate concentration up to 0.8 meq/gm, an addition liquid such as
 acetone, uncapped PEG, DMSO, or acetone, and a contrast agent such as
 meglumine. The prepolymer may include a fluorine containing diisocyanate.
 The prepolymer may include a polyfunctional amine such as lysine to end
 isocyanate reactivity, applied after tissue contact. The prepolymer may
 include the step of: heating the compound to a temperature to between
 about 65-80 degrees C.; and adding the compound to mammalian body tissue.
 The invention also includes a method for treating urinary incontinence in a
 mammal comprising the steps of: delivering a composition comprising a
 biocompatible prepolymer, a biocompatible solvent, and a contrast agent to
 the periurethral tissue of the mammal wherein said prepolymer reacts with
 all available water at the site of injection and further wherein the
 delivery results in a polymer matrix of fixed volume formed in situ in the
 periurethral tissue thereby reducing urinary incontinence in the mammal.
 The method may include the step of: delivering the composition into the
 periurethral tissue by an endoscopic process, that is via an endoscope.
 The invention also include a method for the delivery of a composition which
 composition includes a biocompatible prepolymer, a biocompatible solvent,
 and a water soluble contrast agent to the periurethral tissue of a mammal,
 which tissue already had deposited therein with an initial amount of the
 composition which method comprises: visualizing the position of the
 deposited composition in the periurethral tissue; delivering a prepolymer
 composition to the periurethral tissue of a mammal containing said
 deposited composition; reacting the biocompatible polymer with all
 available water at the delivery site; and delivering additional polymer
 matrix bonds to the the deposited mass incrementally to controllably
 increase the resistance of the flow of urine from the bladder. The method
 may include the step of: visualizing the deposition of compound by
 selection of one of the processes of the group consisting of: direct
 visualization, feel, fluoroscopy or ultrasound.
 The invention also includes the method for further treating urinary
 incontinence in a mammal, comprising the step of: implanting a first
 biocompatible polymer matrix to a periurethral tissue site of a mammal;
 implanting a second biocompatible polymer matrix to said site at least one
 day after said first implanted biocompatible polymer matrix has been
 implanted at said site, wherein said implanted biocompatible polymer
 matrix is visualized, and a delivery device is directed to the site, and
 wherein an additional volume of prepolymer solution is delivered
 incrementally to the site, the prepolymer solution bonding to the
 periurethral tissue and a previously formed biocompatible polymer mass.
 The invention also includes a method for treating GERD in a mammal
 comprising the steps of: delivering a composition comprising a
 biocompatible prepolymer, a biocompatible solvent, and a contrast agent to
 the gastroesophogeal tissue of the mammal wherein the prepolymer reacts
 with all available water at the site of injection and further wherein the
 delivery results in a polymer matrix of fixed volume formed in situ in the
 esophageal tissue thereby reducing GERD in the mammal. The method may
 include the step of: delivering the composition into the gastroesophageal
 tissue by an endoscope.
 The invention also includes a method for the delivery of a composition
 which composition includes a biocompatible prepolymer, a biocompatibte
 solvent, and a water soluble contrast agent to the gastroesophageal tissue
 of a mammal, which tissue already had deposited therein with an initial
 amount of the deposited composition, which method comprises: visualizing
 the position of the deposited composition in the esophageal tissue;
 delivering a prepolymer composition to the esophageal tissue of a mammal
 containing the deposited composition; reacting the biocompatible polymer
 with all available water at the delivery site; and delivering additional
 polymer matrix bonds to the deposited composition incrementally to
 controllably increase the resistance of the flow of gastric juices from
 the stomach of the mammal. The method may include the step of: visualizing
 the deposited composition by selection of one of the processes of the
 group consisting of: direct visualization, feel, fluoroscopy or
 ultrasound.
 The invention also includes a method for further treating GERD in a mammal,
 comprising the step of: implanting a first biocompatible polymer matrix to
 a gastroesophageal tissue site of a mammal; implanting a second
 biocompatible polymer matrix to the site at least 24 hours (one day) after
 the first implanted biocompatible polymer matrix has been implanted at the
 site, wherein the implanted biocompatible polymer matrix is visualized;
 and directing a delivery device to the site, and incrementally delivering
 an additional volume of prepolymer solution incrementally to the site, the
 additional volume of prepolymer solution bonding to esophageal tissue and
 any previously formed biocompatible polymer mass.

DETAILED DESCRIPTION OF THE INVENTION
 This invention is directed to methods for augmenting tissue, and
 specifically for treating urinary incontinence and GERD, which methods
 comprise delivery of a composition comprising a biocompatible
 tissue-reactive prepolymer, an inert viscosity lowering medium, and a
 contrast agent to a tissue site.
 The tissue-reactive prepolymer types disclosed here differ from inert
 polymers, in that they bond with tissue to form a bulk inert polymer in
 situ.
 The term "biocompatible tissue-reactive prepolymer" refers to prepolymers
 which, in the amounts employed, are after curing non-toxic, non-peptidyl,
 non-migratory, chemically inert, and substantially non-immunogenic when
 used internally in a mammal and which are substantially insoluble in the
 periurethral tissue. The bonded biocompatible polymer does not
 substantially change volume over time and does not migrate to distant
 organs within the body.
 A uniquely flexible, biocompatible, non-biologic tissue bond can be
 produced by cross-linking hydrated polymer gels to nitrogenous components
 found in living tissue. The hydrated tissue augmentation is formed by
 reacting polymeric monomer units with tissue, at least 75% of which are
 oxyethylene-based diols or polyols with molecular weight exceeding 10,000.
 The prepolymer is preferably comprised of hydroxyl groups of diols or
 polyols substantially all capped by polyisocyanate, where non-polymerized
 polyisocyanate accounts for less than 4% (v/v) of the adhesive tissue
 augmentation injectable. Amines in the tissue serve to polymerize tissue
 with the adhesive tissue augmentation injectable. Water mixed or acquired
 at the bond site generates additional amine through reaction with
 polyisocyanate and serves to polymerize the bulk of the bond.
 The addition of an organic liquid lacking an accessible OH, and preferably
 one formed in the Krebs cycle can be used to adjust cure time and
 prepolymer viscosity. The organic liquid must be completely miscible with
 the prepolymer, and essentially polar. When the addition liquid is
 miscible it also becomes trapped permanently within the hydrated polymer
 matrix formed when injected into tissue. Trapping the addition liquid is
 essential to preserving hydrated polymer matrix volume. Liquids not
 occurring naturally within the body may also be used, such as glycerol,
 but these liquids may not share the same biocompatibility.
 The addition of aqueous solution to the prepolymer just before application
 represent and embodiment of the present invention, and in the case of
 aliphatic prepolymer compositions, typically provide long (&gt;10 minutes)
 pot life. Where "pot life" is defined as that period of time just after
 introduction of the aqueous component to the polyol and just before
 gelation sufficient to prevent ejection through the treatment needle.
 Any of the previously known tissue bulking compositions can be combined
 with the present invention. Some of these must be added just prior to
 injection, such as any of several animal components, be they autologous or
 zenologous. In particular, collagen may be used. All of the inert
 additives may be added during device packaging, and form the original
 ingredients of the composition. For example, teflon particles and fibers,
 pyrolytic carbon coated beads, silicone beads, etc may be added to the
 composition. Also, tissue initiators may be added. For example,
 beta-glucan may be added to promote fibrosis. However, all of the above
 additions are likely to promote tissue reaction, and therefore must be
 considered less biocompatible.
 The diols and polyols used in the tissue bond predominately or exclusively
 are polyoxyalkylene diols or polyols whose primary building blocks are
 ethylene oxide monomer units. Preferably, 75% of the units should be
 ethylene oxide. Other adhesive tissue augmentation injectable systems may
 contain proportions of propylene oxide or butylene oxide units in the
 polyols. The use of these constituents is specifically avoided in the
 present invention.
 To obtain desirable tissue augmentation injectable viscosity and bond
 strength high molecular weight ethylene oxide-based diol and polyols are
 used to prepare the tissue augmentation injectable. The diol or polyol
 molecular weight prior to capping with polyisocyanate should be at least
 8000 MW, preferably greater than 10,000 MW. Triols (trihydroxy compounds)
 in the preparation of the polyols are the precursors to preparation of the
 prepolymer of this invention. There are many suitable triols:
 triethanolamine, trimethylolpropane, trimethylolethane, and glycerol.
 Alternatively, tetrols may be used. Triol- or tetrol-based polyols are
 capped with polyfunctional isocyanate, preferably a diisocyanate.
 Alternatively, diols may be used. High molecular weight polyethylene
 glycols are satisfactory. Diols are to be end capped with diisocyanates in
 addition with cross-linking compounds. Polyfunctional amines and
 isocyanates are suitable as cross-linking agents. Mixtures of diols and
 polyols are also suitable.
 The prepolymer of this invention is formed by reacting the hydroxyl groups
 of the diols or polyols with polyisocyanates. The choice of the
 polyisocyanate will depend on factors well known in the art, including
 precursor choice, cure time, and mechanical properties of the tissue bond
 formed by reacting the prepolymer with tissue.
 The choice of precursor is not independent of the choice of polyisocyanate.
 The choice must afford sufficient cross-linking to the tissue so as not to
 compete detrimentally with internal cross-linking initiated with the
 addition of water to the bond. This competition can be favorably biased in
 favor of the tissue bonding reaction by heating the tissue augmentation
 injectable, reducing its viscosity by addition of solvents, or adding
 macroscopic hygroscopic fillers. The choice may also afford rapid bulk
 polymerization--typically less than 60 seconds. However, in the case of
 urethral or esophageal bulking a longer pot time is desired, typically
 about 15-30 minutes. Increase in bulk polymerization time can be
 accomplished by adding acetone or selecting a less reactive polyisocyante.
 Aliphatic or cycloaliphatic polyisocyanates are preferred in the above
 embodiments because they result in more biocompatible prepolymers.
 Examples of suitable (listed in descending order of suitability)
 polyfunctional isocyanates are found in the literature, and include the
 following and commonly obtained mixtures of the following:
 9,10-anthracene diisocyanate
 1,4-anthracenediisocyanate
 benzidine diisocyanate
 4,4'-biphenylene diisocyanate
 4-bromo-1,3-phenylene diisocyanate
 4-chloro-1,3-phenylene diisocyanate
 cumene-2,4-diisocyanate
 Cyclohexylene-1,2-diisocyanate
 Cyclohexylene-1,4-diisocyanate
 1,4-cyclohexylene diisocyanate
 1,10-decamethylene diisocyanate
 3,3'dichloro-4,4'-biphenylene diisocyanate
 4,4'diisocyanatodibenzyl
 2,4-diisocyanatostilbene
 2,6-diisocyanatobenzfuran
 2,4-dimethyl1,3-phenylene diisocyanate
 5,6-dimethyl1,3-phenylene diisocyanate
 4,6-dimethyl1,3-phenylene diisocyanate
 3,3'-dimethyl-4,4'diisocyanatodiphenylmethane
 2,6-dimethyl-4,4'-diisocyanatodiphenyl
 3,3'-dimethoxy-4,4'-diisocyanatodiphenyl
 2,4-diisocyantodiphenylether
 4,4'-diisocyantodiphenylether
 3,3'-diphenyl-4,4'-biphenylene diisocyanate
 4,4'-diphenylmethane diisocyanate
 4-ethoxy-1,3-phenylene diisocyanate
 Ethylene diisocyanate
 Ethylidene diisocyanate
 2,5-fluorenediisocyanate
 1,6-hexamethylene diisocyanate
 Isophorone diisocyanate
 4-methoxy-1,3-phenylene diisocyanate
 methylene dicyclohexyl diisocyanate
 m-phenylene diisocyanate
 1,5-naphthalene diisocyanate
 1,8-naphthalene diisocyanate
 polymeric 4,4'-diphenylmethane diisocyanate
 p-phenylene diisocyanate
 p,p',p"-triphenylmethane triisocyanate
 Propylene-1,2-diisocyanate
 p-tetramethyl xylene diisocyanate
 1,4-tetramethylene diisocyanate
 2,4,6-toluene triisocyanate
 trifunctional trimer (isocyanurate) of isophorone diisocyanate
 trifunctional biuret of hexamethylene diisocyanate
 trifunctional trimer (isocyanurate) of hexamethylene diisocyanate
 Bulk curing of the tissue bond of this invention is achieved by using
 stoichiometric amounts of reactants. The isocyanate-to-hydroxyl group
 ratio should be as low as possible without inhibiting bonding function,
 typically 2+/-10%. Higher ratios achieve adequate bonds but result in
 excessive amounts of monomer in the bond. The time period used to cap the
 polyol or diol is dependent on the polyisocyanate used. Methods for
 polyisocyanate capping of polyols are well known.
 In forming the tissue augmentation, organic solvents are usefully present
 during the polymerization with tissue to enable a greater tolerance of
 excessive isocyanate that may disrupt hydrated polymer formation. Varying
 the amount of solvent also varies the viscosity of the tissue augmentation
 injectable. The porosity of the tissue bond can be decreased by reducing
 the viscosity of the prepolymer, and conversely. Useful solvents are
 ethanol, acetonitrile, saline and acetone.
 A prepolymer-aqueous solution may be premixed in ratios up to 1:1 to
 initiate polymerization and curing. Alternative, the prepolymer may be
 delivered to the site and then followed with an injection of difunctional
 amine to initiate bulk polymerization. Such methods are useful in
 obtaining near instantaneous tackiness and fixation.
 The prepolymer-to-aqueous solution ratio should be 1:1 to about 20:1,
 preferably about 5:1 to about 10:1. The ratio is often chosen such that
 the in situ cured mass approximates the surround tissue modulus. Bulk
 polymerization time, bond strength and bond porosity increases in the
 preferred ratios when the prepolymer content increases.
 The implantability of the cured prepolymer of this invention relates to the
 bond's ability to present a surface of water to adjacent tissue. When the
 prepolymers of this invention are used in contact with water-containing
 tissues, the ethylene oxide segments of the bond attract and complex with
 water molecules. Consequently, the surface presented to living cells is
 predominately a layer of water. The protective layer of water renders the
 underlying synthetic polymeric tissue bond noninteractive with proteins.
 Consequently, the cured prepolymer does not remove or denature proteins
 from the environment in which it is implanted.
 The prepolymer may also be mixed with a contrast agent or radiopaque
 material. The contrast agent may become part of the polymer matrix as are
 the water miscible types, or suspended in the polymer matrix as in the
 water insoluble type. Water soluble contrast agents include metrizamide,
 iopamidol, iothalamate sodium, iodomide sodium, and meglumine. Examples of
 water insoluble contrast agents include tantalum, tantalum oxide, gold,
 tungsten, platinum, and barium sulfate.
 The examples that follow are given for illustrative purposes and are not
 meant to limit the invention described herein.
 EXAMPLE I
 Preparation of Tissue Augmentation Injectable A
 Pluracol V10.TM. (BASF, propylene oxide/ethylene oxide) is to be deionized
 and dried. 2167.3 g deionized Pluracol V10 are to be mixed with 148.5 g
 isophorone diisocyanate (IPDI) and 0.84 g Santonox R.TM. (Monsanto
 Chemical Co.) and heated at 67 degrees C. under dry nitrogen for 17 days,
 or until isocyanate concentration reaches 0.4 meq/g. The appearance is
 clear, with a viscosity of 78,000 cps at 22.degree. C. and 1.1 g/ml at
 22.degree. C. and free IPDI of approximately 1.5-3% (wt.). The mixture is
 decanted and 100 g of meglumine and 100 g of acetone are mixed until in
 solution. The resulting prepolymer will be radiopaque, low viscosity and
 form a hydrated matrix trapping acetone when mixed with water or injected
 into living tissue.
 EXAMPLE II
 Preparation of Tissue Augmentation Injectable B
 Pluracol V10.TM. (BASF, propylene oxide/ethylene oxide) is to be deionized
 and dried. 2170 g deionized Pluracol V10 are to be mixed with 82.4 g IPDI,
 150 ml butadione. The mixture is to be heated to 67 degrees C. under dry
 nitrogen until isocyanate concentration reaches 0.2 meq/g.
 EXAMPLE III
 Preparation of Tissue Augmentation Injectable C
 AO-MAL20.TM. (Shearwater Polymers, Inc., copolymer of M-PEG Allyl Ether and
 Maleic anhydride) is to be deionized and dried. 900 g deionized TPEG 15000
 are to be mixed with 45 g IPDI and 0.6 g Santonox R. To this mixture 500
 ml acetonitrile is to be added to obtain a liquid. The mixture is to be
 heated to 72 degrees C. under dry nitrogen until isocyanate concentration
 reaches 0.13 meq/g. To this mixture an additional 100 ml of 0.9% saline is
 added and 50 g barium sulfate.
 EXAMPLE IV
 Preparation of Tissue Augmentation Injectable D
 TPEG1000.TM. (Union Carbide Corp., polyethylene glycol) is to be deionized
 and dried. 1475 g deionized TPEG 10000 are to be mixed with 102.3 g IPDI
 and 0.79 g Santonox R. The reactants are to be dissolved in 87 ml
 acetonitrile. The mixture is to be heated to 72 degrees C. under dry
 nitrogen until isocyanate concentration reaches 0.43 meq/g. To this
 mixture 100 g of dry glycerol are added and mixed.
 EXAMPLE V
 Preparation of Tissue Augmentation Injectable E
 BASF#46889 (polyethylene glycol) is to be deionized and dried. 567 g
 deionized BASF#46889 are to be mixed with 59 g IPDI and 0.54 g Santonox R.
 The reactants are to be dissolved in 572 ml acetonitrile. The mixture is
 to be heated to 67 degrees C. under dry nitrogen until isocyanate
 concentration reaches 0.46 meq/g.
 EXAMPLE VI
 Preparation of Tissue Augmentation Injectable F
 TPEG 10000.TM. (Union Carbide Corp., polyethylene glycol) is to be
 deionized and dried. 475 g deionized TPEG 10000 are to be mixed with 102.3
 g IPDI and 0.79 g Santonox R. The mixture is to be heated to 72 degrees C.
 under dry nitrogen until isocyanate concentration reaches 0.46 meq/g. To
 this mixture 100 g of acetone are to be added to form a liquid at room
 temperature.
 EXAMPLE VII
 Preparation of Tissue Augmentation Injectable G
 Polyethylene glycol (PEG) (12000 MW) is to be deionized and dried. 0.03
 moles PEG are to be mixed with 0.15 moles trimethylolpropane and heated to
 60 degrees C. The heated mixture is to be combined, by stirring for one
 hour, with 0.11 moles commercial isomer blend of xylene diisocyanate.
 Stirring is to continue until the isocyanate concentration reaches an
 asymptote of 0.39 meq/g.
 EXAMPLE VIII
 Preparation of Tissue Augmentation Injectable H
 Polyethylene glycol (PEG) (28000 MW) is to be deionized and dried. 0.04
 moles PEG are to be mixed with 0.2 moles trimethylolpropane and heated to
 60 degrees C. The heated mixture is to be combined, by stirring for one
 hour, with 0.1 moles commercial isomer blend of xylene diisocyanate.
 Stirring is to continue until the isocyanate concentration reaches an
 asymptote of 0.2 meq/g.
 EXAMPLE IX
 Preparation of Tissue Augmentation Injectable I
 An adhesive tissue augmentation injectable is to be formed by following
 Example I, substituting an equivalent molar amount of commercial isomer
 blend of Toluene diisocyanate for the IPDI. The isocyanate content is to
 reach 0.8 meq/g. The appearance should be a light amber liquid of about
 10,000 cps, containing less than 3.5% free TDI.
 EXAMPLE X
 Preparation of Tissue Augmentation Bond A
 Five grams of Adhesive tissue augmentation injectable A are to be mixed
 with 1 g water for about 1 minute. The pot time of such a tissue
 augmentation injectable mixture is about 1 hr. The mixture is to be
 applied to living tissue. The cross-linked structure of tissue and tissue
 augmentation injectable A are Tissue Bond A.
 EXAMPLE XI
 Preparation of Tissue Augmentation Bond F
 Adhesive tissue augmentation injectable G is to be applied directly to a
 tissue surface and mixed at the site with liquid present to reach a
 mixture of 1:5 water-to- tissue augmentation injectable. The cure time is
 30-60 seconds. The cross-linked structure of tissue and Adhesive tissue
 augmentation injectable G are Tissue Bond F.
 EXAMPLE XII
 Preparation of Tissue Augmentation Bond C
 Adhesive tissue augmentation injectable I is to be heated to 65-80 degrees
 C. and applied directly to a tissue surface. The cure time is 30 seconds.
 The cross-linked structure of tissue and Adhesive tissue augmentation
 injectable I are Tissue Bond C.
 EXAMPLE XIII
 Preparation of Tissue Augmentation Bond D
 The tissue surface is to be swabbed with 3% hydrogen peroxide until the
 surface appears white. The treated surface is to be swabbed dry. Adhesive
 tissue augmentation injectable I is to be heated to 65-80 degrees C. and
 applied directly to a tissue surface. Preferably the adhesive layer on the
 tissue measures less than 1 mm in thickness. A second coat of saturated
 lysine solution is to be sprayed, but not mixed on the site. Fixing power
 is achieved immediately. The cross-linked structure of activated tissue,
 Adhesive tissue augmentation injectable I, and lysine are Tissue Bond D.
 EXAMPLE XIV
 Preparation of Tissue Augmentation Bond E
 Example XIII if followed except Adhesive tissue augmentation injectable I
 is premixed with equal volumes of acetonitrile and sprayed on the
 activated site. The cross-linked structure is adhesive immediately, but
 the acetonitrile is allowed to evaporate to create Tissue Bond E, a thin
 sealing layer.
 The principles, preferred embodiments and modes of operation of the present
 invention have been described in the foregoing specification. The
 invention that is intended to be protected herein, however, is not to be
 construed as limited to the particular forms disclosed, since these are to
 be regarded as illustrative rather than restrictive. Variations and
 changes may be made by those skilled in the art without departing from the
 spirit of the invention.
 Methods Specific to the treatment of Urinary Incontinence and GERD of the
 present Invention are as follows:
 The Tissue Augmentation Prepolymers described above can be employed in
 methods for treating urinary incontinence and GERD in mammals. In the
 methods for treatment of incontinence the composition is injected into the
 periurethral tissue via conventional catheter or needle technology using,
 for example, endoscopic or cystoscopic techniques. The injection can be
 accomplished with a puncture needle or spinal needle introduced directly
 or periurethrally with a spinal needle placed percutaneously at the
 introitus and positioned in the tissue adjacent to the urethra.
 Alternatively, the periurethral tissue can be exposed surgically and the
 composition injected directly. Alternatively, the submucosa can be
 injected using a William's cystoscopic needle.
 Alternatively, the gastroesophageal junction may be bulked by injection
 into the esophageal wall via access inside the esophagus.
 Injection of the composition into the target tissue causes the composition
 to gel but not change volume. The formed polymer matrix in the target
 tissue maintains the tissue in the swelled state, restricts the urethral
 or esophageal orifice and impedes involuntary flow of urine or gastric
 juices from the bladder or stomach.
 The formed injection does not change shape, and is fully elastic. Collagen
 and particulate injections can change shape, and consequently suffer
 diminished effectiveness.
 The particular amount of composition employed is dictated by the level of
 pre-existing support of the target tissue and not dependent upon the
 concentration of the prepolymer in the composition or the rate of matrix
 formation.
 The presence of the contrast agent can assist monitoring of the delivery
 while it takes place by fluoroscopy or ultrasound. Monitoring the delivery
 of the bulking composition is important to ensure the optimal location in
 the target tissue is found and an optimal size of polymer matrix is
 formed.
 The components of the injectable composition intended to aid in delivery
 ideally do not react with the isocyanate component. Similarly, delivery
 devices should not react with the injectable. Polyethylene syringes and
 stainless steel hypodermic needles are acceptable in the presence of the
 composition described herein. Other materials compatible with the
 compositions described here include polyolefins, fluoropolymers, or
 silicones.
 The methods of this invention are preferably practiced using a kit
 containing a sealed syringe loaded with a prepolymer composition and a
 needle of suitable length and gauge. Either the needle produces an opening
 in the sealed syringe to allow delivery of its contents, or the syringe is
 sealed with a removable cap. The cap being one with a Luer Lok.TM.
 interface with the syringe.