AU2007200560A1 - In situ bulking device - Google Patents

Description

P/00/011 Regulation 3.2

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION FOR A DIVISIONAL PATENT

ORIGINAL

TO BE COMPLETED BY APPLICANT Name of Applicant: PRAXIS LLC Actual Inventor: Michael T. MILBOCKER Address for Service: CALLINAN LAWRIE, 711 High Street, Kew, Victoria 3101, Australia Invention Title: IN SITU BULKING DEVICE The following statement is a full description of this invention, including the best method of performing it known to us:- 07/02/07,Document15,1 In Situ Bulking Device oo Background of the Invention Field of the invention

INO

t The invention relates to methods and substances comprising a S biocompatible, non-degradable polymer of stable volume for the purpose of S augmenting mammalian tissue.

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 crosslinked 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.

US Pat. No. 5,785,642 (Wallace et al.) describes a 3-part injectable 00 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.

US 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.

US 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.

US Pat. No. 5,922,025 (Hubbard) describes a permanent, CI biocompatible material for soft tissue augmentation. The biocompatible material comprises a matrix of smooth, round, finely divided, substantially 00 spherical particles of a biocompatible ceramic material. However, 0D prevention of migration of the ceramic material is not described.

US Pat. No. 5,976,526 (Atala) describes treatment of vesicoureteral 0 reflux, incontinence and other defects using an injectable of bladder cells mixed with a liquid polymeric material. This material is susceptible to biodegradation.

US 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.

US Patent No. 5,709,854 (Griffith-Cima et al) describes a cell polymeric solution that self-crosslinks, 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 c-i is exercise to strengthen the pelvic floor muscles. If these exercises are ineffective, open surgical repair of the bladder neck is often attempted. Such 00 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, 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 Obstet. Gynaecol., 45:67-71(1938)). This material was not successful in treating incontinence and pulmonary infarction was an observed complication. Paraffin (Acta Urol. Beig., 23:259-262(1955)) and other sclerosing solutions (Urol. nt., 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 to 86% in some studies (JUrol.,ll1:180-183(19 74 Br.JUrol.,55:208- 210(1983); BMJ 228;192 (1984); J.Urol.,(Paris), 62:39-41(1987); CI Br.J.Urol., 62:39-41 (1988); Aust. N.Z.JSurg., 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); BrJ.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 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 00 the stomach.

In addition to the need for an immobilized, volume-constant IND 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 examiple, 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.

The present application is a divisional application of Australian Patent Application No. 2001296315, the specification of which is herein incorporated by reference.

Brief Summary of the Invention (Ni This invention is directed toward all applications where bulking of tissue provides a functional or aesthetic result. Accordingly, in one of its 00 method aspects, this invention is directed to a method for treating urinary incontinence in a mammal, which method comprises delivery of a single coymposition 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.

lIt 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 builking 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 builking 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 0 S fluoroscopic contrast for noninvasive visualization during and after Simplantation.

oo 0 It is another object of this invention that the prepolymer composition be gamma sterilizable without appreciable crosslinking of the prepolymer or 0 altering its hydrated tissue bond functionality.

SThe 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 tissueaugmentation 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 00 0 prepolymer units may preferably be aliphatic or aromatic isocyanate-capped oxyethylene-based diols or polyols. The molecular weight of the diols or 0 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-trifluoro-1,3 phenylene diisocyanate. The polyisocyanate may be a mixture of Toluene diisocyanate and tetrafluoro-1,3-phenylene diisocyanate. The polyisocyanate may be a mixture of diphenylmethane diisocyanate and 6-chloro 2 4 ,5-trifluoro-1,3 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-tohydroxyl 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

O

N compound may further comprise a contrast agent comprised of meglumine.

The hydrated, biocompatible tissue-augmentation may further be comprised oo 00 of a low molecular weight uncapped polyethylene glycol, consisting of PEG 300 as a solvent. The hydrated, biocompatible tissue-augmentation 0compound 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 tissueaugmentation 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 0 cN polyisocyanate at an isocyanate-to-hydroxyl ratio of about 1.5 to 2.5 so that S all of the hydroyl groups of said diols or polyols are capped with 00 0 polyisocyanate and the resulting prepolymer has an isocyanate concentration S 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 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.

0 C The prepolymer may include a fluorine containing diisocyanate. The prepolymer may include a polyfunctional amine such as lysine to end 0 isocyanate reactivity, applied after tissue contact. The prepolymer may IsD include the step of: heating the compound to a temperature to between about S65-80 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 S deposited composition in the periurethral tissue; delivering a prepolymer S composition to the periurethral tissue of a mammal containing said deposited S composition; reacting the biocompatible polymer with all available water at 00 the delivery site; and delivering additional polymer matrix bonds to the the N deposited mass incrementally to controllably increase the resistance of the 0 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 0 c- comprising the steps of: delivering a composition comprising a 00 biocompatible prepolymer, a biocompatible solvent, and a contrast agent to the gastroesophogeal tissue of the mammal wherein the prepolymer reacts 0 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 0esophageal 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 biocompatible 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 r- juices from the stomach of the mammal. The method may include the step ci of: visualizing the deposited composition by selection of one of the L processes of the group consisting of: direct visualization, feel, fluoroscopy 00 or ultrasound.

The invention also includes a method for further treating GERD in a Smammal, 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 tissuereactive prepolymer, an inert viscosity lowering medium, and a contrast l agent to a tissue site.

The tissue-reactive prepolymer types disclosed here differ from inert 0 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 nonimmunogenic 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% 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 c-i the bond site generates additional amine through reaction with polyisocyanate and serves to Polymerize the bulk of the bond.

00 0 The addition of an organic liquid lacing an accessible OHK and 0 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 prepolyrner just before application -represent and embodiment of the present invention, and in the case of aliphatic prepolymer compositions, typically provide long 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 00 the composition. For example, teflon particles and fibers, pyrolytic carbon coated beads, silicone beads, etc may be added to the composition. Also, 0 tissue initiators may be added. For example, beta-glucan may be added to S 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 S compounds) in the preparation of the polyols are the precursors to c-N preparation of the prepolymer of this invention. There are many suitable triols: triethanolamine, trimethylolpropane, trimethylolethane, and glycerol.

00oo 0 Alternatively, tetrols may be used. Triol- or tetrol-based polyols are capped with polyfunctional isocyanate, preferably a diisocyanate.

8 Alternatively, diols may be used. High molecular weight polyethylene 0 glycols are satisfactory. Diols are to be end capped with diisocyanates in addition with crosslinking compounds. Polyfunctional amines and isocyanates are suitable as crosslinking 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 crosslinking to the tissue so as not to compete detrimentally with internal crosslinking 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 iN macroscopic hygroscopic fillers. The choice may also afford rapid bulk AC polymerization typically less than 60 seconds. However, in the case of 00 urethral or esophageal bulking a longer pot time is desired, typically about 15-30 minutes. Increase in bulk polymerization time can be accomplished by Sadding 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-l,4-diisocyanate 1,4-cyclohexylene diisocyanate ci1, 1O-decanaethylene dilsocyanate 3, V'dichloro-4,4'-biphenylene diisocyanate 00 4,4' diisocyanatodibenzyl 2,4-diisocyanatostilbene 2,6-diisocyanatobenzfuran 2.-iehc1.-hnln dioynt 2,4-dimethyl- 1,3 -phenylene dilsocyanate 5,6-dimethyl- 1,3 -phenylene dilsocyanate 4,6'-dimethyl- ,3-hnyediisocyanatelehe 3,3 -dimethyl-4,4 'diisocyanatodiphenylmthn 2,6'-dimethoyl-4,4'-diisocyanatodipheny 3,3 -dimeoytho4,diiscynatodphny 4, 4 '-diisocyantodiphenyeter 3,3 '-diphenyl-4,4 '-biphenylene dilsocyanate 4,4 '-diphenylinethane diisocyanate, 4-ethoxy-1 ,3-phenylene diisocyanate Ethylene dilsocyanate Ethylidene diisocyanate 2 l, 6 -hexamethylene dilsocyanate Isophorone dilsocyanate 4 -methoxy-l,3-phenylene diisocyanate, 00 0 methylene dicyclohexyl diisocyanate m-phenylene, dilsocyanate diisocyanate l, 8 -naphthalene diisocyanate, Polymeric 4 4 '-diphenylmethane dilsocyanate p-phenylene dilsocyanate PIP', P"-triphenylmethane triisocyanate Propylene-i 2 -diisocyanate p-tetramethyl xylene dilsocyanate 1 4 -tetramethylene dilsocyanate, 2 4 ,6-toluene truisocyanate trifunctional trimer (isocyanurate) of isophorone diisocyanate trifunctional biuret of hexamethylene diisocyanate tifunctional triner (isocyanurate) of hexamethylene dfisocyanate Bulk curing of the tissue bond of this invention is achieved by using stoichiometric amounts of reactants. The isocyanate-to..hydroxyj 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 00 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 ci preferred ratios when the prepolymer content increases.

The implantability of the cured prepolymer of this invention relates to 00 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.

I

S Example I: Preparation of Tissue Augmentation Injectable A Pluracol V10 T (BASF, propylene oxide/ethylene oxide) is to be deionized S and dried. 2167.3 g deionized Pluracol V10 are to be mixed with 148.5 g 00 0 isophorone diisocyanate (IPDI) and 0.84 g Santonox RTM (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 oC and 1.1 g/ml at 22 oC and free IPDI of approximately 1.5-3% 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 Iniectable B Pluracol V10T (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.

N Example II: Preparation of Tissue Augmentation Iniectable C A AO-MAL20 T (Shearwater Polymers, Inc., copolymer of M-PEG Allyl 00oo 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 0mixture 500 ml acetonitrile is to be added to obtain a liquid. The mixture is Sto 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 Iniectable

D

TPEG10000 T (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 100g 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 oo 0 deionized BASF#46889 are to be mixed with 59 g IPDI and 0.54 g Santonox 0 R. The reactants are to be dissolved in 572 ml acetonitrile. The mixture is to 0 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 TPEG10000 m (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.

0 Stirring is to continue until the isocyanate concentration reaches an asymptote of 0.39 meq/g.

00 Example VIII: Preparation of Tissue Augmentation Iniectable

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 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 oo 0 augmentation injectable mixture is about lhr. The mixture is to be applied to Sliving tissue. The crosslinked structure of tissue and tissue augmentation 0 injectable A are Tissue Bond A.

C 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 water-to- tissue augmentation injectable. The cure time is 30-60 seconds.

The crosslinked 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 crosslinked structure of tissue and Adhesive tissue augmentation injectable

I

are Tissue Bond C.

Example XIM: Pretparation 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 00 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 crosslinked structure of activated tissue, Adhesive tissue augmentation injectable I, and lysine are Tissue Bond D.

Example MIV: Preparation of Tissue Augmentation Bond E Example XMI if followed except Adhesive tissue augmentation injectable

I

is premi xed with equal volumes of acetonitrile and sprayed on the activated site. The crosslinked 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 00 0 of the present Invention are as follows: 0The 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 b-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 c-i from the bladder or stomach.

The formed injection does not change shape, and is fulfly elastic.

00 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 c-.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 0 silicones.

SThe methods of this invention are preferably practiced using a kit oo 0 containing a sealed syringe loaded with a prepolymer composition and a S needle of suitable length and gauge. Either the needle produces an opening kn 0 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 LokTM interface with

C

I the syringe.

Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification, they are to be interpreted as specifying the presence of the stated features, integers, steps or components referred to, but not to preclude the presence or addition of one or more other feature, integer, step, component or group thereof

Claims (28)

1. A hydrated, biocompatible tissue-augmentation compound comprised F of: living tissue, body derived fluids, at least one NCO-terminated 00 Shydrophilic urethane prepolymer derived from an organic polyisocyanate, Sand oxyethylene-based diols or polyols comprised essentially all of 0 hydroxyl groups capped with polyisocyanate.

2. The hydrated, biocompatible tissue-augmentation compound of claim 1 in which substantially all of said prepolymer units are aliphatic or aromatic isocyanate-capped oxyethylene-based diols or polyols.

3. The hydrated, biocompatible tissue-augmentation compound of claim 1 in which the molecular weight of said diols or polyols prior to capping with polyisocyanate is at least 3,000.

4. The hydrated, biocompatible tissue-augmentation compound of claim 1 in which said polyisocyanate is a Toluene diisocyanate. The hydrated, biocompatible tissue-augmentation compound of claim 1 in which said polyisocyanate is isophorone diisocyanate.

6. The hydrated, biocompatible tissue-augmentation compound of claim 1 in which said polyisocyanate is a mixture of Toluene diisocyanate and 6- chioro, 2,4,5-trifluoro-1,3 phenylene dilsocyanate. 00 0 7. The hydrated, biocompatible tissue-augmentation compound of claim 1 in which said polyisocyanate is a mixture of Toluene diisocyanate and tetrafluoro- 1,3-phenylene dilsocyanate.

8. The hydrated, biocompatible tissue-augmentation compound of claim 1 in which said polyisocyanate is a mixture of diphenylmethane diisocyanate and 6-chioro, 2,4,5-trifluoro-1,3 phenylene diisocyanate.

9. The hydrated, biocompatible tissue-augmentation compound of claim 1 in which said polyisocyanate is a mixture of diphenylinethane diisocyanate and tetrafluoro- 1,3-phenylene diisocyanate. The hydrated, biocompatible tissue-augmentation compound of claim 1 in which said polyisocyanate is para-phenylene disocyanate.

11. The hydrated, biocompatible tissue-augmentation compound of claim 1 in which the diols or polyols are capped with polyisocyanate wherein said isocyanate-to-hydroxyl group ratio is between 1.5 and oo 00

12. The hydrated, biocompatible tissue-augmentation compound of claim 1 in which the isocyanate concentration in the prepolymer units is between S0.05 and 0.8 milliequivalents per gram.

13. The hydrated, biocompatible tissue-augmentation compound of claim 1 that further comprises a biocompatible solvent comprised of acetone to control viscosity and cure time.

14. The hydrated, biocompatible tissue-augmentation compound of claim 1 that further comprises a contrast agent comprised of meglumine. The hydrated, biocompatible tissue-augmentation compound of claim 1 that further comprises a low molecular weight uncapped polyethylene glycol, consisting of PEG 300 as a solvent.

16. The hydrated, biocompatible tissue-augmentation compound of claim 1 c that further comprises a contrast agent and a biocompatible solvent in combination. 00 oo 0 17. The hydrated, biocompatible tissue-augmentation compound of claim 1 In that further comprises a physiological saline.

18. The hydrated, biocompatible tissue-augmentation compound of claim 4 that is comprised of between 10-30% physiologic saline.

19.The hydrated, biocompatible tissue-augmentation compound of claim that is comprised of 10-20% physiologic saline. hydrated, biocompatible tissue-augmentation compound of claim 1 that includes an injectable material selected from the group comprised of: collagen, silicone, teflon, or pyrolytic carbon coated beads.

21. 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- 0 CN- water ratio of 3:1 to 20:1, said prepolymer prepared by the steps of: S selecting diols or polyols from oxyethylene-based diols or polyols having 00 San average molecular weight of 3,000 to about 30,000, and S(b) reacting said 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.

22. The hydrated tissue-augmentation compound method of claim 21 wherein said diols or polyols are oxyethylene-based diols or polyols.

23. The hydrated tissue-augmentation compound method of claim 21 wherein said diols and polyols of step are dissolved in an organic solvent selected from the group comprising acetonitrile or acetone.

24. The hydrated tissue-augmentation compound method of claim 21 which includes a solution of non-body derived water, including a salint solution containing 0.9% NaCl. The hydrated augmentation compound of claim 21 in which said 00 O prepolymer-to-water ratio is between 3:1 to 20:1. 0 26. The hydrated augmentation of claim 21 including the step of: 0 washing the bond with a polyfmnctional diamine to end In 0 isocyanate reactivity. N

27. 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, said 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.

28. The prepolymer of claim 27 including a fluorine containing 00 C N diisocyanate. oo

29.The prepolymer of claim 27 including a polyfunctional amine such as lysine to end isocyanate reactivity, applied after tissue contact. In r-- 0 30.The prepolymer of claim 27, including the step of: heating said compound to a temperature to between about 65-80 degrees C; and adding said compound to mammalian body tissue.

31. 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 said delivery results in a polymer matrix of fixed volume formed in situ in the periurethral tissue thereby reducing urinary incontinence in the mammal.

32. The method of claim 31 including the step of: O delivering said composition into the periurethral tissue by an endoscopic process. 00 S 33. 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 Salready had deposited therein with an initial amount of said 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 said biocompatible polymer with all available water at the delivery site; and delivering additional polymer matrix bonds to the said deposited mass incrementally to controllably increase the resistance of the flow of urine from the bladder.

34. The method according to claim 33 including the step of: O N visualizing said deposition of compound by selection of one of the C processes of the group consisting of: direct visualization, feel, 00 fluoroscopy or ultrasound. O In S 35. A 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 said site, and wherein an additional volume of prepolymer solution is delivered incrementally to said site, said prepolymer solution bonding to said periuretheral tissue and a previously formed biocompatible polymer mass.

36. A method for treating GERD in a mammal comprising the steps of: o delivering a composition comprising a biocompatible prepolymer, a biocompatible solvent, and a contrast agent to the gastroesophogeal tissue 00 0 of the mammal wherein said prepolymer reacts with all available water at 0 the site of injection and further wherein said delivery results in a polymer In Smatrix of fixed volume formed in situ in the esophageal tissue thereby reducing GERD in the mammal.

37. The method of claim 36 including the step of: delivering said composition into the gastroesophageal tissue by an endoscope.

38. 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 gastroesophageal tissue of a mammal, which tissue already had deposited therein with an initial amount of said deposited composition, which method comprises: visualizing the position of said deposited composition in the esophageal tissue; delivering a prepolymer composition to the esophageal tissue of a 0 Smammal containing said deposited composition; Sreacting said biocompatible polymer with all available water at the 00 0 delivery site; and 0 delivering additional polymer matrix bonds to the said deposited In 0 composition incrementally to controllably increase the resistance of the flow of gastric juices from the stomach of the mammal.

39. The method according to claim 38 including the step of: visualizing said deposited composition by selection of one of the processes of the group consisting of: direct visualization, feel, fluoroscopy or ultrasound. 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 said site at least one day after said first implanted biocompatible polymer matrix has been implanted at said site, wherein said implanted biocompatible 0 polymer matrix is visualized; and directing a delivery device to said site, and incrementally o delivering an additional volume of prepolymer solution incrementally to 0 said site, said additional volume of prepolymer solution bonding to 0 1 0 esophageal tissue and any previously formed biocompatible polymer 0 Smass. DATED this 8 th day of February, 2007 PRAXIS LLC By their Patent Attorneys: CALLINAN LAWRIE