(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2007/0184087 A1
`Voigts et al.
`(43) Pub. Date:
`Aug. 9, 2007
`
`US 2007 O184087A1
`
`(54) POLYSACCHARIDE COMPOSITIONS FOR
`USE IN TISSUE AUGMENTATION
`
`(75) Inventors: Robert Voigts, Wind Lake, WI (US);
`Dale Devore, Chelmsford, MA (US)
`Correspondence Address:
`FOLEY & LARDNER LLP
`321 NORTH CLARK STREET
`SUTE 28OO
`CHICAGO, IL 60610-4764 (US)
`
`(73) Assignee: Bioform Medical, Inc.
`
`(21) Appl. No.:
`
`11/650,696
`
`(22) Filed:
`
`Jan. 8, 2007
`
`Related U.S. Application Data
`(63) Continuation-in-part of application No. 1 1/348,028,
`filed on Feb. 6, 2006, now abandoned.
`Publication Classification
`
`(51) Int. Cl.
`(2006.01)
`A 6LX 3L/77
`(2006.01)
`A6F 2/02
`(52) U.S. Cl. .............................................. 424/423: 514/57
`
`ABSTRACT
`(57)
`A composition of matter and method for preparation of a
`tissue augmentation material. A polysaccharide gel compo
`sition is prepared with a programmable rheology for a
`particular selected application. The method includes prepar
`ing a polymeric polysaccharide in a buffer to create a
`polymer Solution or gel Suspending particles in the gel and
`selecting a rheology profile for the desired tissue region.
`
`Exhibit 1042
`Prollenium v. Allergan
`
`

`

`Patent Application Publication Aug. 9, 2007 Sheet 1 of 16
`
`US 2007/0184087 A1
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`Patent Application Publication Aug. 9, 2007 Sheet 2 of 16
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`US 2007/0184087 A1
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`Patent Application Publication Aug. 9, 2007 Sheet 3 of 16
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`

`

`Patent Application Publication Aug. 9, 2007 Sheet 4 of 16
`
`US 2007/0184087 A1
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`Patent Application Publication Aug. 9, 2007 Sheet 5 of 16
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`US 2007/0184087 A1
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`FIG. 9
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`

`

`Patent Application Publication Aug. 9, 2007 Sheet 6 of 16
`
`US 2007/0184087 A1
`
`10000
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`

`

`Patent Application Publication Aug. 9, 2007 Sheet 7 of 16
`
`US 2007/0184087 A1
`
`
`
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`100
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`

`

`Patent Application Publication Aug. 9, 2007 Sheet 8 of 16
`
`US 2007/0184087 A1
`
`- 30% CahA-3.25 CMC; 15% glycerin
`-
`--- 30% CahA-2.6% CMC; 1.5% glycerin
`-...-- 40% CahA-2.6% CMC; 1.5% glycerin
`
`10000000
`
`
`
`1000000-S
`
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`10000
`
`f Hz)
`
`FIG. 15
`
`

`

`Patent Application Publication Aug. 9, 2007 Sheet 9 of 16
`
`US 2007/0184087 A1
`
`- 30% CahA-3.25 CMC; 15% glycerin
`--- 30% CahA-2.6% CMC; 1.5% glycerin
`--...- 40% CahA-2.6% CMC; 1.5% glycerin
`
`1OOOO
`
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`
`f Hz)
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`FG 16
`
`

`

`Patent Application Publication Aug. 9, 2007 Sheet 10 of 16
`
`US 2007/0184087 A1
`
`- 30% CahA-3.25 CMC; 15% glycerin
`--- 30% CahA-2.6% CMC; 1.5% glycerin
`-...-...- 40% CaFA-2.6% CMC; 1.5% glycerin
`
`
`
`f Hz)
`
`FIG. 17
`
`

`

`Patent Application Publication Aug. 9, 2007 Sheet 11 of 16
`
`US 2007/0184087 A1
`
`- 30% CaHA-3.25 CMC; 15% glycerin
`--- 30% CahA-2.6% CMC; 1.5% glycerin
`--- 40% CahA-2.6% CMC; 1.5% glycerin
`
`
`
`f Hz)
`
`FIG. 18
`
`

`

`Patent Application Publication Aug. 9, 2007 Sheet 12 of 16
`
`US 2007/0184087 A1
`
`- 30% CahA-3.25 CMC; 15% glycerin
`--- 30% CahA-2.6% CMC; 1.5% glycerin
`--- 40% CahA-2.6% CMC; 1.5% glycerin
`
`
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`
`

`

`Patent Application Publication Aug. 9, 2007 Sheet 13 of 16
`
`US 2007/0184087 A1
`
`0000"#7
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`

`Patent Application Publication Aug. 9, 2007 Sheet 14 of 16
`
`US 2007/0184087 A1
`
`
`
`

`

`Patent Application Publication Aug. 9, 2007 Sheet 15 of 16
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`US 2007/0184087 A1
`
`
`
`FIG.22 (Prior Art)
`
`

`

`Patent Application Publication Aug. 9, 2007 Sheet 16 of 16
`
`US 2007/0184087 A1
`
`
`
`
`
`FIG. 23a
`PRIOR ART
`
`
`
`PRIOR ART
`
`FIG.23b
`
`PRIOR ART
`
`
`
`FIG.23d
`
`PRIOR ART
`
`

`

`US 2007/0184087 A1
`
`Aug. 9, 2007
`
`POLYSACCHARDE COMPOSITIONS FOR USE IN
`TISSUE AUGMENTATION
`
`CROSS-REFERENCE TO RELATED PATENT
`APPLICATION
`0001. The present application is a continuation-in-part of
`U.S. patent application Ser. No. 1 1/348,028, filed Feb. 6,
`2006 and incorporated herein by reference in its entirety.
`
`FIELD OF THE INVENTION
`0002 The present invention relates generally to tissue
`augmentation, and more particularly to injection of resorb
`able, biocompatible, Solid composites to correct and aug
`ment soft tissue defects with specific application for cos
`metic augmentation of tissues.
`
`BACKGROUND OF THE INVENTION
`0003. There are a number of non-resorbable, particle
`based compositions used for permanent correction or aug
`mentation of soft tissue defects or augmentation for cos
`metic purposes. Each composition is associated with certain
`advantages and disadvantages.
`0004 Silicone gel was frequently used to treat dermal
`defects, such as wrinkles, folds, and acne scars in the 1970's
`and 1980s but has since been prohibited from use in these
`applications. Silicone was frequently associated with
`chronic inflammation, granuloma formation, and allergic
`reactions.
`0005 Teflon paste is a suspension of polytetrafluoroeth
`ylene particles in glycerin. This composition was primarily
`used for vocal fold augmentation and was associated with
`granuloma formation.
`0006 Bioplastics composed of polymerized silicone par
`ticles dispersed in polyvinylpyrrolidone. This composition
`has been withdrawn from commercial application due to
`frequent chronic inflammation and tissue rejection.
`0007 Polymethylmethacrylate (PMMA) microspheres
`having a diameter of 20-40 um and Suspended in a bovine
`collagen dispersion have been described by Lemperle (U.S.
`Pat. No. 5,344,452). This composition has been used as a
`biocompatible alloplastic for tissue augmentation. Since the
`composition contains collagen from a bovine source, skin
`testing is required. In addition, the composition is associated
`with sterilization challenges; the bovine collagen dispersion
`is damaged by Standard terminal sterilization techniques,
`including heat and gamma irradiation. PMMA is also labile
`to heat Sterilization conditions.
`0008 Sander, etal. (U.S. Pat. No. 5,356,629) describes
`bone repair compositions comprised of a plurality of bio
`compatible particles dispersed in a matrix selected from a
`group consisting of hyaluronic acid, cellulose ethers, col
`lagen and others. The biocompatible particles include Suit
`able nonbioabsorbable material derived from xenograft
`bone, homologous bone, autologous bone, hydroxyapatite
`and polymethylmethacrylate. Cellulose ethers include
`hydroxypropylmethylcellulose, methylcellulose, and car
`boxymethylcellulose and mixtures thereof. Sodium car
`boxymethylcellulose is the preferred form of carboxymeth
`ylcellulose. Biocompatible particles ranged from about 64%
`
`to 94% by weight. Matrix components ranged from about
`6% to about 35% by weight. Compositions were formulated
`into putty for bone repair.
`0009 Lawin, etal. (U.S. Pat. No. 5.451.406) describes a
`biocompatible composition consisting of stable micropar
`ticles carried in a lubricative suspension, Solution, fluid or
`gel. The microparticles are carbon-coated Substrate particles
`comprised of stainless Steel, titanium, titanium alloys and
`their oxides. The carrier is selected from a group comprised
`of hyaluronic acid, polyvinylpyrrolidone, dextran, glycerol,
`polyethylene glycol, Succinylated collagen, liquid collagen
`or other polysaccharides. The carrier is preferably com
`prised of polymeric chains off-D glucose. Compositions are
`intended to strengthen bulk-up, or otherwise augment tissue
`sites.
`0010 Injectable suspensions of bio-active glass particles
`in a dextran derivative have been described by Hench, et.al.
`(U.S. Pat. No. 6,190.684). Smooth or rough particles of
`bioactive glass may be spherical or irregular and Smooth or
`rough and range in size from about 10 to 350 microns. The
`Viscous dextran can be mixed with bioactive glass particles
`in a ratio of about 35:65 to about 65:35 by weight glass to
`dextran to form an injectable composite. The composition
`may be injected using 16 to 23 gauge needles for tissue
`augmentation.
`0011 Vogel, et al., (U.S. Pat. Nos. 6,436,424 and 6,660,
`301) describe injectable, swellable microspheres. The
`microspheres comprise sodium acrylate polymer, acryla
`mide polymer, acrylamide derivative polymer or copolymer,
`Sodium acrylate and vinyl alcohol copolymer, vinyl acetate
`and acrylic acid ester copolymer, vinyl acetate and methyl
`maleate
`copolymer,
`isobutylene-maleic
`anhydride
`crosslinked copolymer, starch-acrylonitrile graft copolymer,
`crosslinked sodium polyacrylate polymer, crosslinked poly
`ethylene oxide, or mixtures thereof. The compositions con
`tain microspheres in amounts ranging from about 10% to
`about 90% by weight and the biocompatible carrier from
`about 10% to about 90% by weight.
`0012 Compositions containing resorbable particles dis
`persed in a polysaccharide carrier have been previously
`described.
`0013 Synthetic, resorbable microspheres composed of
`polylactides, such as polylactic acids (PLA), polyglycolides
`(PGA) or copolymers of PLA and PGA have been dispersed
`in a carrier gel (U.S. Pat. No. 6,716.251). The carrier gels
`included preparations of carboxymethylcellulose (CMC) or
`hydroxypropylmethylcellulose (HPMC) or synthetic hyalu
`ronic acid. Such compositions were prepared for use as
`Subcutaneous or dermal injection, intended for use in
`humans in reparative or plastic Surgery and in aesthetic
`dermatology. Concentrations of CMC ranged from 0.1% to
`7.5%, preferably from 0.1% to 5%. Mixtures of PLA in
`CMC were freeze dried and sterilized by gamma irradiation.
`0014) Hubbard (U.S. Pat. Nos. 5,922,025; 6,432,437;
`6,537,574; and 6.558,612) describes an implantable or
`injectable soft tissue augmentation material comprised of
`Substantially spherical, biocompatible, Substantially non
`resorbable ceramic particles Suspended in biocompatible,
`resorbable fluid lubricant comprised of aqueous glycerin and
`sodium carboxylmethylcellulose. Ceramic particles in the
`composition can vary from 15% to 50% by volume. Prepa
`
`

`

`US 2007/0184087 A1
`
`Aug. 9, 2007
`
`rations having more than 50% ceramic particles become
`Viscous and care must be taken to select an injection
`apparatus. Compositions containing ceramic particles of
`35% to 45% can easily be injected through an 18 gauge
`needle. A 28 gauge needle may be used depending on the
`tissue sites for augmentation. Sterilization was accom
`plished by autoclaving at temperatures of about 115° C. to
`130° C., and preferably about 120° C. to 125° C.
`0015 Tucker, etal. (U.S. Pat. No. 6,461,630) describes
`terminally sterilized osteogenic devices intended for implan
`tation to induce bone formation. The devices contains a
`biologically active, osteogenic protein in a carrier comprised
`of collagen, hydroxyapatite, tricalcium phosphate, combi
`nations of collagen with hydroxyapatite, tricalcium phos
`phate, all of which may be supplemented with carboxym
`ethylcellulose. Sterilization was accomplished by gamma
`irradiation after drying the composition comprised of osteo
`genic protein and biocompatible carrier.
`0016 Ronan, etal. (U.S. Pat. No. 6,387.978) describes
`shaped-medical devices, e.g. stents, having improved
`mechanical properties and structural integrity. The devices
`comprise shaped polymeric hydrogels which are both ioni
`cally and non-ionically crosslinked and which exhibit
`improved structural integrity after selective removal of the
`crosslinking ions. Process for making such devices are also
`disclosed wherein an ionically crosslinkable polymer is both
`ionically and non-ionically crosslinked to form a shaped
`medical device. When implanted in the body, selective
`in-vivo stripping of the crosslinking ions produces a softer,
`more flexible implant.
`0017 Asius, et al., (U.S. Pat. No. 6,716.251) describe
`implants for Subcutaneous or intradermal injection. The
`implants contain microparticles of lactic acid and glycolic
`acid in a gel composed of 0.1-7.5% by weight carboxym
`ethylcellulose. Microparticles range in size from 5 to less
`than 150 micrometers and in a concentration from 50 to 300
`g/l.
`0018 Boume, et al., (U.S. Pat. No. 7,131,997) describes
`a method for treating tissue by placing spherical polymer
`particles in tissue. The particles composed of polyvinyl
`alcohol can include a polysaccharide Such as alginate.
`0019. As can be seen from the prior art, carboxymethyl
`cellulose and other polysaccharides are examples of material
`used in gel or Solution form for a variety of medical and
`non-medical applications. Sodium carboxymethylcellulose
`(“CMC) is cellulose reacted with alkali and chloroacetic
`acid. It is one of the most abundant cellulose polymers
`available. It is water soluble and biodegradable and used in
`a number of medical and food applications. It is also
`commonly used in textiles, detergents, insecticides, oil well
`drilling, paper, leather, paints, foundry, ceramics, pencils,
`explosives, cosmetics and adhesives. It functions as a thick
`ening agent, a bonder, stabilizer, water retainer, absorber,
`and adhesive.
`0020. A number of literature references describe car
`boxymethylcellulose and other ionic polysaccharides as
`being viscoelastic and pseudoplastic. See, for example:
`(Andrews G P. Gorman S P Jones D. S., Rheological
`Characterization of Primary and Binary Interactive Bioad
`hesive Gels Composed of Cellulose Derivatives Designed as
`Ophthalmic Viscosurgical Devices, Biomaterials. 2005 Feb
`
`ruary; 26 (5):571-80; Adeyeye MC, Jain AC, Ghorab MK,
`Reilly W J Jr. Viscoelastic Evaluation of Topical Creams
`Containing Microcrystalline Cellulose/sodium Carboxym
`ethyl Cellulose as Stabilizer, AAPS PharmSciTech. 2002: 3
`(2):E8: Lin SY. Amidon G. L. Weiner N D, Goldberg A H.,
`Viscoelasticity of Anionic Polymers and Their Mucociliary
`Transport on the Frog Palate, Pharm. Res. 1993, March: 10
`(3): 411-417: Vais, A E, Koray, T P Sandeep, K. P. Daubert,
`C R. Rheological Characterization of Carboxymethylcellu
`lose Solution Under Aseptic Processing Conditions, J. Food
`Science, 2002. Process Engineering 25: 41-62).
`0021. The effects of various parameters on rheology of
`sodium CMC have been described. Viscosity increases with
`increasing concentration, and CMC solutions are pseudo
`plastic and Viscoelastic. Exposure to heat results in a reduc
`tion in viscosity and effects are reversible under normal
`conditions. After long periods of time, CMC will degrade at
`elevated temperatures with permanently reduced Viscosity.
`For example, moderate MW (Aqualon 7 L) CMC heated for
`48 hours at 180° F. will lose 64% of viscosity. CMC is
`relatively stable to changes in pH, and effects of pH on
`viscosity are minimal from pH 7-9. There is some loss of
`viscosity above 10 and some increase below 4. Salts may
`also affect rheology of CMC. Monovalent cations interact to
`form soluble salts. If CMC is dissolved in water and then
`salts are added, there is little effect on viscosity. If CMC is
`added dry to salt Solution, Viscosity can be depressed.
`Polyvalent cations will not generally form crosslinked gels.
`Viscosity is reduced when divalent salts added to CMC
`solution and trivalent salts precipitate CMC.
`0022 Goldberg (U.S. Pat. No. 4,819,671) describes a
`Viscoelastic material for ophthalmic Surgery composed of
`sodium carboxymethylcellulose. Goldberg, et.al. (U.S. Pat.
`No. 5,080,893) and Goldberg etal. (U.S. Pat. No. 5,140,016)
`which are incorporated by reference describe compositions
`for Surgical techniques and tissue-protective Surgery. The
`carboxymethylcelluloses (CMC) useful in combination with
`the method are also of molecular weights greater than
`500,000. A preferred example is a commercially available
`CMC of about 800,000 molecular weight. Such polyelec
`trolyte polysaccharides are especially valuable because of
`the good viscoelastic behavior of aqueous solutions which
`enable the use of lower solution concentrations for effective
`tissue protection; aqueous Solutions with concentrations of
`1-2% or less being used.
`0023 Carlson, et al., (U.S. Pat. No. 5,670,077) incorpo
`rated by reference describe a magnetorheological material
`containing a water-soluble Suspending agent selected from
`the group consisting of cellulose ethers such as sodium
`carboxymethylcellulose, methyl hydroxyethylcellulose and
`other ether derivatives of cellulose; and biosynthetic gums
`Such as Xanthan gum, Welan gum and rhamsan gum, and
`water. The combination of water and an appropriate water
`soluble Suspending agent renders the corresponding magne
`torheological material highly non-Newtonian, thereby inhib
`iting the settling of particles in spite of their high density and
`large size.
`0024 Burdick, C L (U.S. Pat. No. 6,359,040) incorpo
`rated by reference describes compositions having advanta
`geous rheological properties comprising an ionic polymer
`and a viscosity promoter. The invention also relates to
`processes for preparation and use of compositions having
`
`

`

`US 2007/0184087 A1
`
`Aug. 9, 2007
`
`advantageous rheological properties, as well as to compo
`sitions and methods for treating paper. The ionic polymer
`and a viscosity promoter can form an interactive complex of
`Sufficiently high molecular weight to act non-Newtonian.
`The ionic polymer comprises at least one anionic polysac
`charide selected from a group consisting of sodium car
`boxymethylcellulose; sodium carboxymethyl hydroxyethyl
`cellulose; pectin; carrageenan; carboxymethylguar gum,
`Sodium alginate; anionic polyacrylamide copolymers;
`alkali-soluble latex; carboxymethyl methylcellulose; and
`carboxymethyl hydroxypropyl guar.
`0025 Haslwanter; Joseph A. etal. (U.S. Pat. No. 6,841,
`146) incorporated by reference describe spray compositions
`with a reduced tendency to run or drip. The spray compo
`sitions are applied intranasally, as a breath freshener, anal
`gesic sprays for the mouth and pharynx and antiseptic sprays
`for skin application of medicinal or cosmetic compositions.
`The compositions containing a therapeutic or palliative
`agent, water and a mixture of microcrystalline cellulose and
`alkali metal carboxyalkylcellulose. The composition exhib
`its a reduced apparent viscosity while being Subjected to
`shear forces, but a high apparent viscosity while at rest. The
`alkali metal carboxyalkylcellulose comprises Sodium car
`boxymethylcellulose.
`0026 Cash, etal. (U.S. Pat. No. 6,602.994) incorporated
`by reference describe methods for producing derivatized
`microfibrillar polysaccharides, including but not limited to
`cellulose, and a method of modifying the rheological prop
`erties of a composition of matter using derivatized
`microfibrillar cellulose. Derivatized microfibrillar polysac
`charides include carboxymethylcellulose. Rheological prop
`erties were influenced by the degree of substitution,
`microfibrillated cellulose length, concentration, and vehicle.
`Cash et al. states that the subject electrostatically derivatized
`materials provide rheology to aqueous systems over a wide
`range of pH and ionic strength. The insensitivity to pH and
`ionic strength facilitates use where low pH and high salt
`concentrations exist.
`0027 Wallace, et al., (U.S. Pat. No. 5,352,715) describe
`injectable ceramic compositions containing calcium phos
`phate particles with a distribution range from 50 to 250 um
`mixed with an organic gel forming polymer to Suspend the
`particles. The gel forming polymer being described as
`collagen wherein ceramic particles at concentrations
`between 10% and 30% ceramic are mixed with collagen to
`form collagen ceramic implants.
`0028 Freed, etal. (U.S. Pat. No. 5,480,644) describe
`injectable biomaterials for repair and augmentation of the
`anal sphincter. The preferred biomaterials are collagen for
`mulations that may contain ceramic particles in the size
`range of about 50-250 microns.
`0029. The prior art gel materials teachings treat the gel
`merely as a carrier, incidental to the actual augmentation
`function of the gel. As a result, the prior art fails to address
`several problems with current gels. First, the injectable
`materials of the prior art fail to address the specific diffi
`culties in applying implants across a wide range of locations
`in the body and fail to provide the appropriate type of
`implant. For example, current implants can experience
`occlusion, or irregular implantation during the implantation
`procedure when a fine gauge needle is used. While in certain
`applications a fine gauge needle may not be required, it is
`
`Vital to the Success of several applications. In addition, a
`Smaller gauge needle leaves a smaller puncture point, which
`is often desirable to patients. Furthermore, the propensity for
`occlusions often results in uneven, erratic and discontinuous
`implantation, which causes highly undesirable results.
`0030 Second, current implants have failed to address the
`Viscoelastic properties of the implant in the Syringe. Such
`that current implants require a significant amount of force,
`and even irregular levels of force, to extrude the implant
`from the needle, much more so as the needle gauge is
`reduced. This presents fatigue issues for medical profession
`als who may well be performing many injections in a day
`and also makes any given injection more difficult to perform,
`and also perform proper injection amounts and distributions,
`because of the necessity to exert a large amount, or an
`irregular amount of force on the Syringe, while maintaining
`a steady needle during injection.
`0031. Third, current implant materials fail to address the
`wide range of distinctions in the different tissues in which
`the implants are placed. Implants can undergo unwanted
`agglomeration, chemical reaction, phase separation, and
`premature breakdown of the implanted mass into discon
`tinuous variable shapes, all of which can consequently
`manifest different undesirable mechanical properties and
`performance relative to the implant tissue region. It is
`generally understood that biological tissues demonstrate non
`linear Viscoelastic responses to stress and strain. (See, e.g.,
`Shen F. Tay TE, et al., J Biomech Eng. 2006 October; 128
`(5):797-801.) It has also known that tissue expansion creates
`tension to the Surrounding cells and extra cellular matrix
`(ECM) which impacts the biochemical response of the ECM
`and Surrounding cells. (See, Pasyk K, Argenta L., and Hassett
`C., “Quantitative analysis of the thickness of human skin
`and Subcutaneous tissue following controlled expansion
`with a silicone implant, Plastic Recontr Surg, 81:516-523,
`1998; Reihsner R. Balogh B, and Menzel E., “Two-dimen
`sional elastic properties of human skin in terms of an
`incremental model at the in vivo configuration'. Med Eng
`Phys 17: 304-313, 1995). A variety of cell types found in
`ECMs appear to undergo mitosis and biosynthetic produc
`tion of ECMs as a result of tension (Silver F. Siperko L, and
`Seehra G., “Mechanobiology of force transduction in dermal
`tissue, Skin Res Tech 9:3-23, 2003; Silver F and Brandica
`G., “Mechanobiology of cartilage: how do internal and
`external stresses affect mechanochemical transduction and
`elastic storage. Biomechan Model Mechanobiol 1: 219
`238, 2002.) Fluid shear forces have also been reported to
`modulate mechano-chemical transduction processes (Silver
`F. DeVore D, and Siperko, L., “Role of mechanophysiology
`in aging of ECM: effects of changes in mechanochemical
`transduction.” Journal of Applied Physiology 95:2134-2141,
`2003.)
`0032. Therefore, material composition and its associated
`mechanical, chemical, electrical and other physical proper
`ties are important relative to: compatibility and stability at
`the tissue implant site; controlled and proper tissue in
`growth and to implement integration into the tissue,
`immuno-histo tissue response, and mechanical and visual
`appearance. The augmentation performance for the patient
`encompasses proper aesthetic outcome arising from the
`function of the physical components and the chemical
`composition of the composite of gel and particles implant. In
`particular, prior art implants utilizing gels have relied on the
`
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`US 2007/0184087 A1
`
`Aug. 9, 2007
`
`gel as a carrier but have failed to recognize and solve the
`problem of providing an implant with a gel which is
`designed to cooperate with the solid particles to approach
`and/or be compatible with the mechanical properties of the
`tissue into which it is injected and to behave in a symbiotic
`controlled manner when embedded in the tissue.
`0033 Implants using these prior art gels exhibit a ten
`dency to form nodules, in certain tissues, such as lips, or to
`migrate from the desired implantation location, or to
`undergo unwanted and undesired chemical and/or mechani
`cal breakdown, Such as phase separation or formation of
`unwanted geometries and cosmetic appearance in the body.
`None of these are an acceptable result for a patient. Nodule
`formation, as shown in FIGS. 22 and 23, has been previously
`reported for prior art compositions by M. Graivier and D.
`Jansen, “Evaluation of a Calcium Hydoxylapatite-Based
`Implant (Radiesse) for Facial Soft-Tissue Augmentation.”
`Plastic and Reconstructive Surgery Journal, Vol. 118, No. 3s.
`pg. 22s (2006). FIG. 22 illustrates a patient with a prior art
`lip implant that has formed nodules due at least in part to the
`inability of the gel to respond appropriately to at least one of
`the mechanical and/or chemical pressures of the implant
`area. FIG. 23a illustrates a lip nodule excised at 1 month
`after injection of a large Volume of implant to the upper lip.
`Iridescent specks representing calcium hydroxylapatite
`material within extracellular matrix are readily observed.
`FIG. 23b illustrates in cross section, densely packed calcium
`hydroxylapatite material is seen (asterisk), along with areas
`of extra cellular matrix without calcium hydroxylapatite
`accumulation (arrow) (stereo magnification 50). FIG. 23b
`illustrates a microscopic review of specimens showing the
`presence of microspheres (denoted by asterisks) scattered
`throughout the fibrotic extracellular matrix or engulfed
`within giant cells. FIG. 23c is a 20x magnification of FIG.
`23a. FIG. 23d is a 40x magnification of FIG. 23b.
`0034) For some prior art compositions, thick collagenous
`material has been observed to encapsulate individual par
`ticles, which may agglomerate to form larger nodules. The
`implant does form a continuous mass between muscle
`bundles (looks like muscle bundles were pushed apart) and
`particles are surrounded by a thick fibrous ring with thinner
`collagen units integrating between particles. In contrast, it
`has been observed in dermis and mucosal areas that collagen
`integration appears as a continuous weave between particles
`and not as a thick capsule around individual particles. This
`thick collagenous material around individual particles is
`similar to that observed in a lip nodule biopsy (such as FIG.
`23, showing a biopsy of several Such particle groupings).
`This encapsulation is likely related to the continuous bio
`mechanical forces in lip muscle, the elasticity and cohesive
`ness of the material, and accumulation between muscle
`bundles.
`0035. Therefore, there is a need for an improved com
`posite implant which provides for ease of injection through
`Small gauge needles while also providing mechanical and
`chemical properties appropriate to the tissue into which it is
`injected and for the designed end purpose.
`
`SUMMARY OF THE INVENTION
`0036) The present invention is directed to systems and
`methods for tissue augmentation. In particular, the systems
`and methods relate to augmentation implants. In one
`
`embodiment, the implants comprise gels having particles
`Suspended therein. The implants have physical properties
`selected to achieve a desired behavior when implanted. For
`example, it is preferable to replace or augment tissue struc
`ture with a material exhibiting physical properties, including
`rheological, chemical, biological, and mechanical proper
`ties, which are similar to those of the treated tissue and/or
`designed to accommodate tissue ingrowth in a controlled
`a.
`0037. These and other objects, advantages, and features
`of the invention, together with the organization and manner
`of operation thereof, will become apparent from the follow
`ing detailed description when taken in conjunction with the
`accompanying drawings, wherein like elements have like
`numerals throughout the several drawings described below.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`0038 FIG. 1 illustrates a plot of elastic viscous modulus
`and complex viscosity as a function of frequency for the
`composition of Example 1:
`0039 FIG. 2 illustrates a plot of elastic and viscous
`modulus and complex viscosity as a function of frequency
`for the composition of Example 2:
`0040 FIG. 3 illustrates a plot of elastic and viscous
`modulus and complex viscosity as a function of frequency
`for the composition of Example 3:
`0041
`FIG. 4 illustrates a plot of elastic and viscous
`modulus and complex viscosity as a function of frequency
`for the composition of Example 4;
`0042 FIG. 5 illustrates a plot of elastic and viscous
`modulus and complex viscosity as a function of frequency
`for the composition of Example 5:
`0043 FIG. 6 illustrates a plot of elastic and viscous
`modulus and complex viscosity as a function of frequency
`for the composition of Example 6:
`0044 FIG. 7 illustrates a plot of elastic and viscous
`modulus and complex viscosity as a function of frequency
`for the composition of Example 7:
`0045 FIG. 8 illustrates a plot of elastic and viscous
`modulus and complex viscosity as a function of frequency
`for the composition of Example 8:
`0046 FIG. 9 illustrates a plot of elastic and viscous
`modulus and complex viscosity as a function of frequency
`for the composition of Example 9:
`0047 FIG. 10 illustrates a plot of elastic and viscous
`modulus and complex viscosity as a function of frequency
`for the composition of Example 10;
`0048 FIG. 11 illustrates a plot of elastic and viscous
`modulus and complex viscosity as a function of frequency
`for the composition of Example 11:
`0049 FIG. 12 illustrates a plot of elastic and viscous
`modulus and complex viscosity as a function of frequency
`for the composition of Example 12:
`0050 FIG. 13 illustrates a plot of elastic and viscous
`modulus and complex viscosity as a function of frequency
`for the composition of Example 13;
`
`

`

`US 2007/0184087 A1
`
`Aug. 9, 2007
`
`FIG. 14 illustrates a plot of elastic and viscous
`0051
`modulus and complex viscosity as a function of frequency
`for the composition of Example 14;
`0.052
`FIG. 15 illustrates the viscosities for each of the
`materials as sheer rate varies;
`0053 FIG. 16 illustrates the loss modulus for each of the
`materials as sheer rate varies;
`0054 FIG. 17 illustrates the viscosity modulus for each
`of the materials as sheer rate varies;
`0055 FIG. 18 illustrates the tan 8 for each of the mate
`rials as sheer rate varies;
`0056 FIG. 19 demonstrates time dependency of the
`elasticity for varying gel compositions with varying con
`centrations of particles (30% & 40% solids in 2.6 CMC:
`1.5% glycerin carrier vs. 30% solids in a 3.25% CMC: 15%
`glycerin carrier);
`0057 FIG. 20 illustrates the loss modulus G', the elastic
`modulus G" and tan