US20070184087A1

US20070184087A1 - Polysaccharide compositions for use in tissue augmentation

Info

Publication number: US20070184087A1
Application number: US11/650,696
Authority: US
Inventors: Robert Voigts; Dale DeVore
Original assignee: Bioform Medical Inc
Current assignee: Bioform Medical Inc
Priority date: 2006-02-06
Filing date: 2007-01-08
Publication date: 2007-08-09
Also published as: JP2013009979A; TWI483714B; EP2114472A2; US20140010709A1; EP2417990A1; KR20150006084A; KR101572410B1; US20140378549A1; WO2008088381A2; KR20090096751A; TW200829220A; US9352046B2; JP5555292B2; CN101610796A; CN104117091A; US20100041788A1; JP2010515527A; WO2008088381A3; JP2014236970A

Abstract

A composition of matter and method for preparation of a tissue augmentation material. A polysaccharide gel composition is prepared with a programmable rheology for a particular selected application. The method includes preparing 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.

Description

CROSS-REFERENCE TO RELATED PATENT APPLICATION

The present application is a continuation-in-part of U.S. patent application Ser. No. 11/348,028, filed Feb. 6, 2006 and incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates generally to tissue augmentation, and more particularly to injection of resorbable, biocompatible, solid composites to correct and augment soft tissue defects with specific application for cosmetic augmentation of tissues.

BACKGROUND OF THE INVENTION

There are a number of non-resorbable, particle-based compositions used for permanent correction or augmentation of soft tissue defects or augmentation for cosmetic purposes. Each composition is associated with certain advantages and disadvantages.
Silicone gel was frequently used to treat dermal defects, such as wrinkles, folds, and acne scars in the 1970's and 1980's but has since been prohibited from use in these applications. Silicone was frequently associated with chronic inflammation, granuloma formation, and allergic reactions.
Teflon paste is a suspension of polytetrafluoroethylene particles in glycerin. This composition was primarily used for vocal fold augmentation and was associated with granuloma formation.
Bioplastics composed of polymerized silicone particles dispersed in polyvinylpyrrolidone. This composition has been withdrawn from commercial application due to frequent chronic inflammation and tissue rejection.
Polymethylmethacrylate (PMMA) microspheres having a diameter of 20-40 μm 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.
Sander, et.al. (U.S. Pat. No. 5,356,629) describes bone repair compositions comprised of a plurality of biocompatible particles dispersed in a matrix selected from a group consisting of hyaluronic acid, cellulose ethers, collagen and others. The biocompatible particles include suitable nonbioabsorbable material derived from xenograft bone, homologous bone, autologous bone, hydroxyapatite and polymethylmethacrylate. Cellulose ethers include hydroxypropylmethylcellulose, methylcellulose, and carboxymethylcellulose and mixtures thereof. Sodium carboxymethylcellulose is the preferred form of carboxymethylcellulose. 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.
Lawin, et.al. (U.S. Pat. No. 5,451,406) describes a biocompatible composition consisting of stable microparticles 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 comprised of polymeric chains of β-D glucose. Compositions are intended to strengthen bulk-up, or otherwise augment tissue sites.
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.
Vogel, et.al., (U.S. Pat. Nos. 6,436,424 and 6,660,301) describe injectable, swellable microspheres. The microspheres comprise sodium acrylate polymer, acrylamide 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 polyethylene oxide, or mixtures thereof. The compositions contain microspheres in amounts ranging from about 10% to about 90% by weight and the biocompatible carrier from about 10% to about 90% by weight.
Compositions containing resorbable particles dispersed in a polysaccharide carrier have been previously described.
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 hyaluronic 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.
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. Preparations 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 accomplished by autoclaving at temperatures of about 115° C. to 130° C., and preferably about 120° C. to 125° C.
Tucker, et.al. (U.S. Pat. No. 6,461,630) describes terminally sterilized osteogenic devices intended for implantation to induce bone formation. The devices contains a biologically active, osteogenic protein in a carrier comprised of collagen, hydroxyapatite, tricalcium phosphate, combinations of collagen with hydroxyapatite, tricalcium phosphate, all of which may be supplemented with carboxymethylcellulose. Sterilization was accomplished by gamma irradiation after drying the composition comprised of osteogenic protein and biocompatible carrier.
Ronan, et.al. (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 ionically 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.
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 carboxymethylcellulose. Microparticles range in size from 5 to less than 150 micrometers and in a concentration from 50 to 300 g/l.
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.
As can be seen from the prior art, carboxymethylcellulose 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 thickening agent, a bonder, stabilizer, water retainer, absorber, and adhesive.
A number of literature references describe carboxymethylcellulose 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 Bioadhesive Gels Composed of Cellulose Derivatives Designed as Ophthalmic Viscosurgical Devices, Biomaterials. 2005 February; 26 (5):571-80; Adeyeye M C, Jain A C, Ghorab M K, Reilly W J Jr, Viscoelastic Evaluation of Topical Creams Containing Microcrystalline Cellulose/sodium Carboxymethyl Cellulose as Stabilizer, AAPS PharmSciTech. 2002; 3 (2):E8; Lin S Y, 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 Carboxymethylcellulose Solution Under Aseptic Processing Conditions, J. Food Science, 2002. Process Engineering 25: 41-62).
The effects of various parameters on rheology of sodium CMC have been described. Viscosity increases with increasing concentration, and CMC solutions are pseudoplastic and viscoelastic. Exposure to heat results in a reduction 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.
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 et.al. (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 polyelectrolyte 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.
Carlson, et.al., (U.S. Pat. No. 5,670,077) incorporated 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 magnetorheological material highly non-Newtonian, thereby inhibiting the settling of particles in spite of their high density and large size.
Burdick, C L (U.S. Pat. No. 6,359,040) incorporated by reference describes compositions having advantageous rheological properties comprising an ionic polymer and a viscosity promoter. The invention also relates to processes for preparation and use of compositions having advantageous rheological properties, as well as to compositions 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 polysaccharide selected from a group consisting of sodium carboxymethylcellulose; sodium carboxymethyl hydroxyethylcellulose; pectin; carrageenan; carboxymethylguar gum; sodium alginate; anionic polyacrylamide copolymers; alkali-soluble latex; carboxymethyl methylcellulose; and carboxymethyl hydroxypropyl guar.
Haslwanter; Joseph A., et.al. (U.S. Pat. No. 6,841,146) incorporated by reference describe spray compositions with a reduced tendency to run or drip. The spray compositions are applied intranasally, as a breath freshener, analgesic 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 exhibits a reduced apparent viscosity while being subjected to shear forces, but a high apparent viscosity while at rest. The alkali metal carboxyalkylcellulose comprises sodium carboxymethylcellulose.
Cash, et.al. (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 properties of a composition of matter using derivatized microfibrillar cellulose. Derivatized microfibrillar polysaccharides include carboxymethylcellulose. Rheological properties 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.
Wallace, et.al., (U.S. Pat. No. 5,352,715) describe injectable ceramic compositions containing calcium phosphate particles with a distribution range from 50 to 250 μm 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.
Freed, et.al. (U.S. Pat. No. 5,480,644) describe injectable biomaterials for repair and augmentation of the anal sphincter. The preferred biomaterials are collagen formulations that may contain ceramic particles in the size range of about 50-250 microns.
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 difficulties 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.
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 professionals 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.
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 discontinuous 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 T E, 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-dimensional 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 production 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.)
Therefore, material composition and its associated mechanical, chemical, electrical and other physical properties 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 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.
Implants using these prior art gels exhibit a tendency 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 mechanical 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. 23 a 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. 23 b 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. 23 b 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. 23 c is a 20× magnification of FIG. 23 a. FIG. 23 d is a 40× magnification of FIG. 23 b.
For some prior art compositions, thick collagenous material has been observed to encapsulate individual particles, 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 biomechanical forces in lip muscle, the elasticity and cohesiveness of the material, and accumulation between muscle bundles.
Therefore, there is a need for an improved composite 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

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 structure with a material exhibiting physical properties, including rheological, chemical, biological, and mechanical properties, which are similar to those of the treated tissue and/or designed to accommodate tissue ingrowth in a controlled manner.
These and other objects, advantages, and features of the invention, together with the organization and manner of operation thereof, will become apparent from the following 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

FIG. 1 illustrates a plot of elastic viscous modulus and complex viscosity as a function of frequency for the composition of Example 1;
FIG. 2 illustrates a plot of elastic and viscous modulus and complex viscosity as a function of frequency for the composition of Example 2;
FIG. 3 illustrates a plot of elastic and viscous modulus and complex viscosity as a function of frequency for the composition of Example 3;
FIG. 4 illustrates a plot of elastic and viscous modulus and complex viscosity as a function of frequency for the composition of Example 4;
FIG. 5 illustrates a plot of elastic and viscous modulus and complex viscosity as a function of frequency for the composition of Example 5;
FIG. 6 illustrates a plot of elastic and viscous modulus and complex viscosity as a function of frequency for the composition of Example 6;
FIG. 7 illustrates a plot of elastic and viscous modulus and complex viscosity as a function of frequency for the composition of Example 7;
FIG. 8 illustrates a plot of elastic and viscous modulus and complex viscosity as a function of frequency for the composition of Example 8;
FIG. 9 illustrates a plot of elastic and viscous modulus and complex viscosity as a function of frequency for the composition of Example 9;
FIG. 10 illustrates a plot of elastic and viscous modulus and complex viscosity as a function of frequency for the composition of Example 10;
FIG. 11 illustrates a plot of elastic and viscous modulus and complex viscosity as a function of frequency for the composition of Example 11;
FIG. 12 illustrates a plot of elastic and viscous modulus and complex viscosity as a function of frequency for the composition of Example 12;
FIG. 13 illustrates a plot of elastic and viscous modulus and complex viscosity as a function of frequency for the composition of Example 13;
FIG. 14 illustrates a plot of elastic and viscous modulus and complex viscosity as a function of frequency for the composition of Example 14;
FIG. 15 illustrates the viscosities for each of the materials as sheer rate varies;
FIG. 16 illustrates the loss modulus for each of the materials as sheer rate varies;
FIG. 17 illustrates the viscosity modulus for each of the materials as sheer rate varies;
FIG. 18 illustrates the tan δ for each of the materials as sheer rate varies;
FIG. 19 demonstrates time dependency of the elasticity for varying gel compositions with varying concentrations of particles (30% & 40% solids in 2.6 CMC: 1.5% glycerin carrier vs. 30% solids in a 3.25% CMC: 15% glycerin carrier);
FIG. 20 illustrates the loss modulus G′, the elastic modulus G″ and tan δ (G′/G″) for compositions of example 16; and
FIG. 21 illustrates viscosity and tan δ properties for compositions of example 16.
FIG. 22 illustrates a photograph of a patient with a prior art lip implant that has formed nodules.
FIG. 23 a 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. 23 b illustrates, in cross section, densely packed calcium hydroxylapatite material (asterisk), along with areas of extra cellular matrix without calcium hydroxylapatite accumulation (arrow) (stereo magnification 50×). FIG. 23 b 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. 23 c is a 20× magnification of FIG. 23 a. FIG. 23 d is a 40× magnification of FIG. 23 b.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is directed to tissue augmentation implants. In one embodiment, the implants comprise gels having particles suspended, therein for use in various parts of the body. Physical properties of body tissue are closely related to tissue function and in one aspect tissue cells respond to the rheological characteristics (e.g., elasticity) of their microenvironment. Understanding the physical structure and function of tissues is of fundamental and therapeutic interest. It is therefore preferable to replace or augment tissue structure with a material exhibiting physical properties, including rheological, and also chemical, biological, and mechanical properties, similar to those of the treated tissue. The implants therefore provide an opportunity to match the properties of the implant with that of the tissue in which the implant is to be placed. This provides improved tissue compatibility of the implant material and encourages normal cell responsiveness. In addition, the similar behavior of the implant and the surrounding tissue provides for a more natural appearance to the augmented area and also can be designed to provide controlled tissue ingrowth.
Definitions herein include “rheology”, which is the study of the deformation and flow of matter. “Newtonian fluids” (typically water and solutions containing only low molecular weight material), the viscosity of which is indeperident of shear strain rate and a plot of shear strain rate. Non-Newtonian fluid is a fluid in which the viscosity changes with the applied shear force. The rheological outputs that describe a material are typically η, G′, G″, tan δ. The η is the viscosity, which is an indication of the materials measure of the internal resistance of a fluid to deform under shear stress. It is commonly perceived as “thickness”, or resistance to pouring. G′ is the storage modulus, which is an indicator of elastic behavior and reveals the ability of the polymer system to store elastic energy associated with recoverable elastic deformation. G″ is the loss modulus, which is a measure of the dynamic viscous behavior that relates to the dissipation of energy associated with unrecoverable viscous loss. The loss tangent (tan δ) is defined as the ratio of the loss modulus to the storage modulus (G″/G′) and is dimensionless. It is a measure of the ratio of energy lost to energy stored in a cycle of deformation and provides a comparative parameter that combines both the elastic and the viscous contribution to the system. A tan δ greater than 1 means the fluid is more liquid. A tan δ less than 1 means the fluid is more solid.
The biomechanical behavior of biomaterials can be characterized by measuring its rheological properties. The magnitude of the rheological properties has been used to indicate overall tissue shear elasticity, stiffness, and rigidity. Often compared is the ratio of viscous shear modulus to elastic shear modulus called tan δ (tan delta). If a material is purely elastic the tan δ=0. If the material is purely viscous, the tan δ=infinity. All tissues exhibit a tan δ between these two extremes.
Different tissues exhibit unique biomechanical characteristics associated with tissue functions and the effects of tissue properties should be considered when augmenting or replacing these tissues. This invention describes compositions that are formulated to simulate the biomechanical properties of the tissues in which the compositions are injected or implanted and avoid unwanted chemical reactions and phase separation. Many different variables together provide the overall mechanical, chemical and biologic properties of the implant. As such, one may vary each of those components of the implant in order to design an implant with specific controlled in vivo properties.
In one preferred embodiment of the present invention, the implant is a composite injectable into soft tissue. The composite material comprises a biocompatible gel and particles. Prior to and during injection, the gel functions, in part, as a carrier for the particles. In vivo, the gel forms an integral part of the implant, providing the previously described pre-selected mechanical and chemical properties for the implant to achieve the desired article of manufacture.
In one embodiment, the gel includes a polysaccharide gel. Polysaccharides that may be utilized in the present invention include, for example, any suitable polysaccharide within the following classes of polysaccharides: celluloses/starch, chitin and chitosan, hyaluronic acid, hydrophobe modified systems, alginates, carrageenans, agar, agarose, intramolecular complexes, oligosaccharide and macrocyclic systems. Examples of polysaccharides grouped into four basic categories include: 1. nonionic polysaccharides, including cellulose derivatives, starch, guar, chitin, agarose and. dextran; 2. anionic polysaccharides including cellulose derivatives starch derivatives, carrageenan, alginic acid, carboxymethyl chitin/chitosan, hyaluronic acid and xanthan; 3. cationic polysaccharides, including cellulose derivatives, starch derivatives guar derivatives, chitosan and chitosan derivatives (including chitosan lactate); and 4. hydrophobe modified polysaccharides including cellulose derivatives and alpha-emulsan. In one embodiment, the polysaccharide polymer is selected from the group of sodium carboxymethylcellulose, hydroxyethyl cellulose, ethylhydroxyethyl cellulose, carboxymethyl cellulose, carboxyethylhydroxyethyl cellulose, hydroxypropylhydroxyethyl cellulose, methyl cellulose, methylhydroxylmethyl cellulose, methylhydroxyethyl cellulose, carboxymethylmethyl cellulose, and modified derivatives thereof. Preferred polysaccharides for use in the present invention include, for example, agar methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, microcrystalline cellulose, oxidized cellulose, chitin, chitosan, alginic acid, sodium alginate, and xanthan gum. In certain embodiments, more than one material may be utilized to form the gel, for example two or more of the above listed polysaccharides may be combined to form the gel.
In addition, the gel may be crosslinked. Appropriate gel cross linkers include for example: heat, pH, and cross-linking through mono valent, di-valent, and tri-valent cationic interactions. The cross linking ions used to crosslink the polymers may be anions or cations depending on whether the polymer is anionically or cationically cross linkable. Appropriate cross linking ions include but are not limited to cations selected from the group consisting of calcium, magnesium, barium, strontium, boron, beryllium, aluminum, iron, copper, cobalt, and silver ions. Anions may be selected from but are not limited to the group consisting of phosphate, citrate, borate, carbonate, maleate, adipate and oxalate ions. More broadly, the anions are derived from polybasic organic or inorganic acids. Preferred cross linking cations are calcium iron and barium ions. The most preferred cross linking cations are calcium and iron. The preferred cross linking anions are phosphate, citrate and carbonate. Cross linking may be carried out by contacting the polymers with an aqueous solution containing dissolved ions. Additionally, cross-linking could be accomplished through organic chemical modification including: poly-functional epoxy compound is selected from the group consisting of 1,4-butanediol diglycidyl ether (BDDE), ethylene glycol diglycidyl ether (EGDGE), 1,6-hexanediol diglycigyl ether, polyethylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol digylcidyl ether, neopentyl glycol digylcidyl ether, polyglycerol polyglycidyl ether, diglycerol polyglycidyl ether, glycerol polyglycidyl ether, tri-methylolpropane polyglycidyl ether, pentaerythritol polyglycidyl ether, and sorbitol polyglycidyl ether. Additionally, cross-linking could be accomplished through organic chemical modification through the carbonyl or hydroxide functionality of the polysaccharide backbone reaction. In embodiments utilizing more than one type of polymer, the different polymers may crosslink with each other to form further crosslinking.
As shown by the examples 1-14 and data hereinafter, in one embodiment the implant comprises a gel, the tan δ (ratio of the viscosity modulus G″ to the loss modulus G′) of which can be manipulated by adjusting the concentration of salt (in this case potassium phosphate) in NaCMC formulations that are subsequently heat sterilized. In compositions prepared in water, the tan δ is <1 before and after heat treatment, indicative of a non-Newtonian fluid. If the compositions are prepared in dilute salt solutions, the tan δ is <1 before heat treatment and >1 after heat treatment. A tan δ>1 generally indicates a Newtonian fluid. Both dilute salt (in this case monovalent) and heat treatment are needed to convert the composition from a tan δ<1 to a tan δ>1. As the salt concentration increases, the viscosity of the composition is reduced.
A suitable composition for tissue augmentation requires a viscosity that will provide some bulking capability. Therefore, the salt concentration is preferably carefully controlled at relatively low levels, usually less than 100 mM. The addition of glycerin to salt solution reduces the tan δ, i.e. the composition, even after heat treatment, remains non-Newtonian. The tan δ is preferably and usually <1. However, the tan δ of this composition is different from the tan δ of compositions prepared in water without salt. The rheological characteristics of NaCMC can be manipulated by salt, glycerin, and heat treatment. There are numerous references describing effects of heat, pH, and salts on the rheology of CMC compositions.
In one exemplary embodiment, the implant includes particles suspended in the gel. In certain embodiments, the particles are ceramic based composites. Particulate ceramic materials include, but are not limited to, calcium hydroxyapatite, and other suitable materials including, but are not limited to, calcium phosphate-based materials, and the like. Examples include, but are not limited to, tetracalcium phosphate, calcium pyrophosphate, tricalcium phosphate, octacalcium phosphate, calcium fluorapatite, calcium carbonate apatite, alumina-based materials, and combinations thereof. The ceramic particles may be smooth rounded, substantially spherical, particles of a ceramic material embedded in a biocompatible gel material that is continuous, cross linked or in a dehydrated configuration as discussed below. In this embodiment, particles may range in size 20 microns to 200 microns. Preferably the particles range from 20 microns to 120 microns and most preferably from 20 microns to 45 microns. Concentration of ceramic particles ranges from 5% to 65%, by volume, preferably from 10% to 50% by volume and most preferably from 30% to 45% by volume.
The gel of the present invention exhibits characteristics that are modifiable to mimic the physical, chemical, and/or mechanical properties of the implant location. Such characteristics include, but are not limited to, extrusion, rheological physical/mechanical parameters, decomposition rate (chemical and physical), moldability, mechanical performance, and porosity to modulate tissue response. Gel characteristics control varying rates of resorption, as host tissue forms around the slower resorbing ceramic particles.
In one embodiment, the present invention provides a gel capable of supporting solid particles for injection through fine gauge needles and forming an integral and compatible part of the implant (and surrounding bio-environment) once injected. The implant of the present invention is capable of being adapted to mimic the mechanical aspects of the tissue into which it is injected and to exhibit controlled chemical behavior at the implant site. These features can include controlled dissolution, phase and shape stability, and a controlled level of chemical stated stability for the intended implant purpose, but allowing desired tissue in-growth and integration with the tissue itself with limited foreign body response. In particular, the gel of the present invention provides the implant with viscoelastic properties to simulate or mimic the appearance and performance of the tissue into which it is injected while remaining in the desired shape without apparent boundaries.
Slight compositional changes in the gel carrier allows for one to control selection of the biocompatibility parameters described as compared to prior implants, as physical characteristics of the carrier more closely simulate the target tissue in regards to osmolarity, rheology, water content, stress/strain character, while still allowing for homogenous particle suspension of the ceramic composite. Tissue specific proteins may be added to facilitate tissue response either by acceleration (infiltration of extra cellular matrix or collagen) or decreasing the immuno histological response. Such careful selection of these biocompatibility characteristics enable achieving a preselected shape, cosmetic appearance, chemical stability and bioenvironment to achieve stability of the implant or tissue in-growth depending on the application. Increased biocompatibility and biomechanical capability allows for the implant to degrade into compounds native to the body according to a specific degradation profile.
In one embodiment, a decrease in glycerin content has provided for an improved osmolarity range that is more physiological with improved biocompatibility not previously reported in prior art. The implant of the present invention does not rely on high amounts of glycerin to suspend the particles, as prior art gels have done. Despite this, the gels of the present invention are able to suspend a higher concentration of particles than previously taught even in prior art gels which relied heavily on glycerin content. The decrease in glycerin content enables the preferred embodiments to have a osmolarity range of 255 mOs to 600 mOs, preferable 255 mOs to 327 mOs, which is closer to the physiological osmolarity of blood of 280 to 303 mOs and is generally accepted as the range for cellular compatibility. Control of the parameter is one degree of freedom in achieving the above recited selection of a biocompatible implant.
The decrease in glycerin and CMC allows for material rheologies that approach these or other physiological extra cellular matrixes and bodily fluids. The lower viscosity modulus G″ and loss modulus G′ allows for better tissue simulation at stress/strain amplitudes typical to target tissue in the human body that further asserts the improved biocompatibility.
The decrease in glycerin content also enables the preferred embodiments to have a water content range of 57.9% to 70.3% water, which is closer to the physiological dermal water content of 70% in embryonic skin to 60% in age dependent skin. Materials that are intended for injection that are closer to physiological water content of the target tissue creates less osmotic stress to the tissues and cells immediate to the implant.
Another controllable degree of freedom in constructing an implant to be biocompatible, as explained in detail herein before, is control of CMC concentration. The decrease in CMC concentration enables the preferred embodiments to have a thinner supporting gel matrix which allow for more particle movement during the injection and post injection which closer mimics the native tissue. It has been demonstrated that formulation adjustment within the gel allows for increasing the bulking material composition and still maintaining biologically relevant rheological characteristics. This facilitates improved baseline correction, improved durability in the soft tissue corrections while maintaining application standards consistent with the intended application. This creates less regional tissue stress and strain. This facilitates a limited immuno histological response in the form of erythema and edema which enhances recovery time, not previously reported in prior art.
In one embodiment, the gel is carboxymethylcellulose (“CMC”) based with concentration ranges from 0.1% to 10%, by weight, preferably from 1.5% to 5% by weight and most preferably from 2% to 3% by weight. As previously discussed, multiple polymer materials may be mixed to form composite gels with compositional ranges for each component between 0.1% to 5%. Glycerin or the like or other space occupying filler (including ionic components and other organic/inorganic non reactive components) may be added to the composition and range from 0.1% to 5% by weight.
These material compositions of the gel allow for better extrusion characteristics through needle gauges at least as small as 30 gauge without the use of assistance devices, and with less frequency of jamming or occlusion not previously accomplished in prior art. While gels having particles suspended therein will clearly have different extrusion characteristics than if there were no particles, the implants of the present invention having particles suspended in gel exhibit improved extrusion over those of the prior art. As particle size approaches that of the needle, extrusion becomes increasing difficult. However, particle sizes below 75 microns allow for implants of the present invention to be injected through fine gauge needs (such as 30 gauge). The gel is able to suspend the particles as a carrier and allow for less force to extrude the implant with a lower likelihood of occlusion. Material compositions with a higher tan δ in the range of 0.5 to 3.5 and most preferably between 0.5 and 2.0 demonstrate the best performance characteristic for extrusion through needle gauges at least as small as 30 gauge. Material with higher tan δ are more preferable for instances where mobility is the key parameter. Decreasing tan δ creates more stout, moldable implant materials.

Implants described herein may be used in various parts of the body for tissue augmentation. As described herein, the properties of the implant may be modified to match the tissue into which it is to be implanted. For example, soft tissue that can be augmented by the implant includes but is not limited to dermal tissue (folds and wrinkles), lips, vocal folds, mucosal tissues, nasal furrows, frown lines, midfacial tissue, jaw-line, chin, cheeks, and breast tissue. It will be appreciated that each of these areas may exhibit unique mechanical and biological properties as known in the art. For example, the upper and lower lip exhibit continuous mobility and require an implant that provides similar mobility because of the muscle interaction and the decreased need for elasticity. Thus implants exhibiting such characteristics provide for both a higher degree of biocompatibility, mechanical compatibility, and a superior visual effect. As such, the implant may be formulated so as to be specifically designed for implantation within a particular portion of the body for addressing a particular indication. Table 1 illustrates the tan δ for vocal folds and skin in the young and the elderly.

TABLE 1


Tan δ for Intact Tissues

Tissue	Tan δ	Reference

Vocal fold	0.1-0.5	Chan, R W and Titze, I R. 1999. J.
(human)	(0.2-0.5 at low	Acoust. Soc. Am., 106: 2008-2021
	frequency)
	(0.1-0.3 at high
	frequency)
Human Dermis-	0.61	Estimated as ratio of slopes of
23 year old	(strain rate 10%	viscous modulus to elastic modulus
	per minute)	from incremental stress-strain
	1.02	curves (Silver, F H, Seehra, G P,
	(strain rate	Freeman, J W, and DeVore, D P.
	1000% per	2002. J. Applied Polymer Science,
	minute)	86: 1978-1985)
Human Dermis-	0.36	See above
87 year old	(strain rate 10%
	per minute)
	1.16
	(strain rate
	1009% per
	minute)

For example, for addressing indications where the tissue exhibits lower viscosity, such as the lips, an implant having a viscosity of between 100,000 centipoise and 300,000 centipoise at 0.5 Hz with a tan δ between 0.5 and 1 may be used. Likewise, for addressing indications where a higher viscosity implant is desired such as facial contouring in the midfacial area or other areas where the implant preferably provides structural support, an implant having a viscosity of between 300,000 centipoise and 600,000 centipoise with a tan δ between 0.5 and 1 may be used.
The tan δ of human vocal fold tissue ranges from 0.1-0.5 indicative of an elastic material (Chan, R W and Titze, I R, Viscoelastic shear properties of human vocal fold mucosa: Measurement methodology and empirical results”. 1999, J. Acoust. Soc. Am. 106:2008-2021). The tan δ of human skin ranges from 0.36 (older skin) to 0.61 (younger skin) (Calculated from stress-strain data- Silver, F H, Seehra, G P, Freeman, J W, and DeVore, D P. 2002. J. Applied Polymer Science, 86:1978-1985). The tan δ for skeletal muscles exceeds 1.0 indicative of a viscous material. The tan δ for hyaluronic acid ranges from 1.3 to 0.3 as the material demonstrates shear thickening and transitions through tan δ equal to 1 between 1 and 8 rad/s (0.17 to 1.3 Hz) (Fung Y C, 1993 “Biomechanics: Mechanical properties of living tissue”, Second edition, Springer-Verlag, New York, N.Y.). This is important when designing a composition to augment human lips (muscle). There is even a difference in stiffness (more elastic according to Chan and Titze, et. al) between the upper and lower lips and between males and females. The lower lip is stiffer than the upper lip and male lips are stiffer than female lips (Ho, T P, Azar, K, Weinstein, and Wallace, W B. “Physical Properties of Human Lips: Experimental Theoretical Analysis”, 1982. J. Biomechanics. 15:859-866). The present invention describes compositions that can be formulated to a rheology (including tan δ) that more closely simulates the tissue into which the biomaterial is placed.
While not limiting the scope of the invention, human lips are believed to be primarily composed of skeletal muscle surrounded by loose connective tissue covered by stratified keratinized squamous (similar to the stratum comeum of skin). In accordance with the principles of one embodiment of the present invention, a composition with a higher tan δ will result in fewer lip nodules, such nodules are a common problem with prior art implants. Tissue responses to any implant depend on several factors including the chemical composition, physical configuration and biomechanical characteristics of the implant material and on the biomechanical forces of the micro environment of the host tissue. Prior art CaHA/CMC compositions injected into tissues under increased mechanical stress produce more collagenous tissue (which may lead to undesired tissue ingrowth in certain applications) than when implanted in tissues under less mechanical stress. Part of this response is related to the viscoelasticity of the implant. An implant under continuous mechanical stress will react differently depending on the viscoelastic properties of the implant. A highly viscoelastic implant (low tan δ) will continuously undergo shear thinning to a lower viscosity and “recoil” to the initial higher viscosity. This continuous change in implant mechanics may “turn on” or signal host cells to become more active and to produce more collagen than an implant exhibiting more Newtonian rheology (higher tan δ). More Newtonian implants will not undergo the same level of mechanical flux compared to more viscoelastic implants.
Thus, while not limiting the size of the invention a composition with a higher tan δ may reduce the incidence of early nodules (those apparently associated with initial macrophage infiltration to engulf and remove CMC) and of later nodules resulting from excess fibrous tissue surrounding CaHA particles. A less elastic and lower viscosity composition will provide a smoother flowing and more intrudable implant with reduced biomechanical motion to signal host cells. These characteristics should result in fewer nodules.
Any number of medically useful substances for treatment of a disease condition of a patient can be used in the invention by adding the substances to the composition at any steps in the mixing process. Such substances include amino acids, peptides, vitamins, co-factors for protein synthesis; hormones; endocrine tissue or tissue fragments; synthesizers; angiogenic drugs and polymeric carriers containing such drugs; collagen lattices; biocompatible surface active agents, antigenic agents; cytoskeletal agents; cartilage fragments, living cells such as chondrocytes, bone marrow cells, mesenchymal stem cells, natural extracts, transforming growth factor (TGF-beta), insulin-like growth factor (IGF-1); growth hormones such as somatotropin; fibronectin; cellular attractants and attachment agents.
The following non-limiting examples illustrate various aspects of the invention.

EXAMPLE 1

Preparation of 2.3% Sodium CMC Gel in Sterile Water.
Sodium carboxymethylcellulose was prepared in sterile water for injection and adjusted to a pH of from about 7.1 to about 8.0 using potassium hydroxide. The dispersion was mixed in an orbital Ross mixer @1725 RPM for 5 minutes followed by mixing in an orbital Ross mixer @1725 RPM for 40 minutes. while holding a vacuum @ 26 mm Hg or more. The composition was then steam sterilization at 121 degrees C. for times ranging from 3 minutes to 30 minutes. In addition, one sample was sterilized for time intervals between 3 minutes and 30 minutes @ 121 degree C. Results are shown in FIG. 1 where G′ represents the elastic modulus, G″ represents the viscous modulus and η the complex viscosity. The profile shows that G′ and G″ intersect at 0.495 Hz (3.2 Rad/sec). Above this frequency, the composition exhibits non-newtonian solution characteristics (tan δ<1.0).

EXAMPLE 2

Preparation of 2.4% Sodium CMC Gel in Sterile Water.
Sodium carboxymethylcellulose was prepared in sterile water for injection and adjusted to a pH of from about 7.1 to about 8.0 using potassium hydroxide. The dispersion was mixed in an orbital Ross mixer @1725 RPM for 5 minutes followed by mixing in an orbital Ross mixer @1725 RPM for 40 minutes. while holding a vacuum @ 26 mm Hg or more. The composition was then steam sterilization at 121 degrees C. for times ranging from 3 minutes to 30 minutes. In addition, one sample was sterilized for time intervals between 3 minutes and 30 minutes @ 121 degree C. Results are shown in FIG. 2 where G′ represents the elastic modulus, G″ represents the viscous modulus and η the complex viscosity. The profile shows that G′ and G″ intersect at 0.0299 Hz (1.8 Rad/sec) (lower frequency than that shown in FIG. 1). Above this frequency, the composition exhibits non-Newtonian solution characteristics (tan δ<1.0).

EXAMPLE 3

Preparation of 2.5% Sodium CMC Gel in Sterile Water.
Sodium carboxymethylcellulose was prepared in sterile water for injection and adjusted to a pH of from about 7.1 to about 8.0 using potassium hydroxide. The dispersion was mixed in an orbital Ross mixer @1725 RPM for 5 minutes followed by mixing in an orbital Ross mixer @1725 RPM for 40 minutes. while holding a vacuum @ 26 mm Hg or more. The composition was then steam sterilization at 121 degrees C. for times ranging from 12 minutes to 30 minutes. In addition, one sample was sterilized for time intervals between 3 minutes and 12 minutes @121 degree C. Results are shown in FIG. 3 where G′ represents the elastic modulus, G″ represents the viscous modulus and η the complex viscosity. The profile shows that G′ and G″ intersect at 0.157 Hz (1 rad/sec) frequency than shown in FIGS. 1 and 2. Above this frequency, the composition exhibits non-Newtonian solution characteristics (tan δ<1.0).

EXAMPLE 4

Preparation of 2.6% Sodium CMC Gel in Sterile Water.
Sodium carboxymethylcellulose was prepared in sterile water for injection and adjusted to a pH of from about 7.1 to about 8.0 using potassium hydroxide. The dispersion was mixed in an orbital Ross mixer @1725 RPM for 5 minutes followed by mixing in an orbital Ross mixer @1725 RPM for 40 minutes. while holding a vacuum @ 26 mm Hg or more. The composition was then steam sterilization at 121 degrees C. for times ranging from 12 minutes to 30 minutes. In addition, one sample was sterilized for time intervals between 12 minutes and 30 minutes @121 degree C. Results are shown in FIG. 4 where G′ represents the elastic modulus, G″ represents the viscous modulus and η the complex viscosity. The profile shows the G′ and G″ intersect at 0.164 Hz (1.03 rad/sec). Above this frequency, the composition exhibits non-Newtonian solution characteristics (tan δ<1.0).

EXAMPLE 5

Preparation of 2.3% Sodium CMC Gel in Potassium Phosphate Buffer.
Sodium carboxymethylcellulose was prepared in sterile 25 mM to 100 mM potassium phosphate buffer pH and adjusted to a pH of from about 7.2 to about 8.0 using potassium hydroxide. The dispersion was mixed in an orbital Ross mixer @1725 RPM for 5 minutes followed by mixing in an orbital Ross mixer @1725 RPM for 40 minutes while holding a vacuum @26 mm Hg or more. The composition was then steam sterilization at 121 degrees C. for times ranging from 3 minutes to 12 minutes. In addition, one sample was sterilized for time intervals between 3 minutes and 12 minutes @121 degree C. Results are shown in FIG. 5 where G′ represents the elastic modulus, G″ represents the viscous modulus and η the complex viscosity. The profile shows that G′ and G″ intersect at 2.401 Hz (15 rad/sec) (similar to that shown in FIG. 4). Above this frequency, the composition exhibits non-Newtonian solution characteristics (tan δ<1.0).

EXAMPLE 6

Preparation of 2.4% Sodium CMC Gel in Potassium Phosphate Buffer.
Sodium carboxymethylcellulose was prepared in sterile 25 mM to 100 mM potassium phosphate buffer pH and adjusted to a pH of from about 7.2 to about 8.0 using potassium hydroxide. The dispersion was mixed in an orbital Ross mixer @1725 RPM for 5 minutes followed by mixing in an orbital Ross mixer @1725 RPM for 40 minutes while holding a vacuum @26 mm Hg or more. The composition was then steam sterilization at 121 degrees C. for times ranging from 3 minutes to 12 minutes. In addition, one sample was sterilized for time intervals between 3 minutes and 12 minutes @121 degree C. Results are shown in FIG. 6 where G′ represents the elastic modulus, G″ represents the viscous modulus and η the complex viscosity. The profile shows that G′ and G″ intersect at 1.56 Hz. (9.8 rad/sec). Above this frequency, the composition exhibits non-Newtonian solution characteristics (tan δ<1.0).

EXAMPLE 7

Preparation of 2.5% Sodium CMC Gel in Potassium Phosphate Buffer.
Sodium carboxymethylcellulose was prepared in sterile 25 mM to 100 mM potassium phosphate buffer pH and adjusted to a pH of from about 7.2 to about 8.0 using potassium hydroxide. The dispersion was mixed in an orbital Ross mixer @1725 RPM for 5 minutes followed by mixing in an orbital Ross mixer @1725 RPM for 40 minutes while holding a vacuum @26 mm Hg or more. The composition was then steam sterilization at 121 degrees C. for times ranging from 3 minutes to 12 minutes. In addition, one sample was sterilized for time intervals between 3 minutes and 12 minutes @121 degree C. Results are shown in FIG. 7 where G′ represents the elastic modulus, G″ represents the viscous modulus and η the complex viscosity. The profile shows that G′ and G″ intersect at 4.54 Hz (28.5 rad/sec). Above this frequency, the composition exhibits non-Newtonian solution characteristics (tan δ<1.0).

EXAMPLE 8

Preparation of 2.6% Sodium CMC Gel in Potassium Phosphate Buffer.
Sodium carboxymethylcellulose was prepared in sterile 25 mM to 100 mM potassium phosphate buffer pH and adjusted to a pH of from about 7.2 to about 8.0 using potassium hydroxide. The dispersion was mixed in an orbital Ross mixer @1725 RPM for 5 minutes followed by mixing in an orbital Ross mixer @1725 RPM for 40 minutes while holding a vacuum @26 mm Hg or more. The composition was then steam sterilization at 121 degrees C. for times ranging from 3 minutes to 12 minutes. In addition, one sample was sterilized for time intervals between 3 minutes and 12 minutes @121 degree C. Results are shown in FIG. 8 where G′ represents the elastic modulus, G″ represents the viscous modulus and η the complex viscosity. The profile shows that G′ and G″ intersect at 3.61 (22.7 rad/sec). Hz. Above this frequency, the composition exhibits non-Newtonian solution characteristics (tan δ<1.0).

EXAMPLE 9

Preparation of 2.7% Sodium CMC Gel in Potassium Phosphate Buffer.
Sodium carboxymethylcellulose was prepared in sterile 25 mM to 100 mM potassium phosphate buffer pH and adjusted to a pH of from about 7.2 to about 8.0 using potassium hydroxide. The dispersion was mixed in an orbital Ross mixer @1725 RPM for 5 minutes followed by mixing in an orbital Ross mixer @1725 RPM for 40 minutes while holding a vacuum @26 mm Hg or more. The composition was then steam sterilization at 121 degrees C. for times ranging from 3 to 12 minutes. In addition, one sample was sterilized for time intervals between 3 minutes and 12 minutes @121 degree C. Results are shown in FIG. 9 where G′ represents the elastic modulus, G″ represents the viscous modulus and η the complex viscosity. The profile shows that G′ and G″ intersect at 3.49 Hz (21.9 rad/sec) Above this frequency, the composition exhibits non-Newtonian solution characteristics (tan δ<1.0). At this sodium CMC concentration (2.7%) the intersect shifts to a lower frequency than that shown in FIG. 7 (2.5% CMC). The composition still exhibits Newtonian fluid characteristics.

EXAMPLE 10

Preparation of 2.8% Sodium CMC Gel in Potassium Phosphate Buffer.
Sodium carboxymethylcellulose was prepared in sterile 25 mM to 100 mM potassium phosphate buffer pH and adjusted to a pH of from about 7.2 to about 8.0 using potassium hydroxide. The dispersion was mixed in an orbital Ross mixer @1725 RPM for 5 minutes followed by mixing in an orbital Ross mixer @1725 RPM for 40 minutes while holding a vacuum @26 mm Hg or more. The composition was then steam sterilization at 121 degrees C. for times ranging from 3 minutes to 12 minutes. In addition, one sample was sterilized for time intervals between 3 minutes and 12 minutes @121 degree C. Results are shown in FIG. 10 where G′ represents the elastic modulus, G″ represents the viscous modulus and η the complex viscosity. The profile shows that G′ and G″ intersect at 4.88 Hz (30.7 rad/sec). Above this frequency, the composition exhibits non-Newtonian solution characteristics (tan δ<1.0). Since the intersect occurs at the top end frequency, this composition exhibits Newtonian characteristics at nearly all frequencies.

EXAMPLE 11

Preparation of 2.6% Sodium CMC Gel in Potassium Phosphate Buffer and Glycerin.
Sodium carboxymethylcellulose was prepared in sterile 25 mM to 100 mM potassium phosphate buffer adjusted to a pH of from about 7.2 to about 8.0 using potassium hydroxide and containing up to 1% glycerin. The dispersion was mixed in an orbital Ross mixer @1725 RPM for 5 minutes followed by mixing in an orbital Ross mixer @1725 RPM for 40 minutes while holding a vacuum @26 mm Hg or more. The composition was then steam sterilization at 121 degrees C. for times ranging from 3 minutes to 12 minutes. In addition, one sample was sterilized for time intervals between 3 minutes and 12 minutes @121 degree C. Results are shown in FIG. 11 where G′ represents the elastic modulus, G″ represents the viscous modulus and η the complex viscosity. The profile shows that G′ and G″ intersect at 1.254 Hz (7.8 rad/sec). Above this frequency, the composition exhibits non-Newtonian solution characteristics (tan δ<1.0). The addition of glycerin to sodium CMC gel in potassium phosphate significantly affects the rheology of the composition, changing it from a fundamentally Newtonian fluid to a non-Newtonian fluid above a frequency of about 1.0.

EXAMPLE 12

Preparation of 2.7% Sodium CMC Gel in Potassium Phosphate Buffer and Glycerin.
Sodium carboxymethylcellulose was prepared in sterile 25 mM to 100 mM potassium phosphate buffer adjusted to a pH of from about 7.2 to about 8.0 using potassium hydroxide and containing up to 1% glycerin. The dispersion was mixed in an orbital Ross mixer @1725 RPM for 5 minutes followed by mixing in an orbital Ross mixer @1725 RPM for 40 minutes while holding a vacuum @26 mm Hg or more. The composition was then steam sterilization at 121 degrees C. for times ranging from 3 minutes to 12 minutes. In addition, one sample was sterilized for time intervals between 3 minutes and 12 minutes @121 degree C. Results are shown in FIG. 12 where G′ represents the elastic modulus, G″ represents the viscous modulus and η the complex viscosity. The profile shows that G′ and G″ intersect at 1.158 Hz (7.2 rad/sec). Above this frequency, the composition exhibits non-Newtonian solution characteristics (tan δ<1.0). The addition of glycerin to sodium CMC gel in potassium phosphate significantly affects the rheology of the composition, changing it from a fundamentally Newtonian fluid to a non-Newtonian fluid above a frequency of about 1.0.

EXAMPLE 13

Preparation of 2.8% Sodium CMC Gel in Potassium Phosphate Buffer and Glycerin.
Sodium carboxymethylcellulose was prepared in sterile 25 mM to 100 mM potassium phosphate buffer adjusted to a pH of from about 7.2 to about 8.0 using potassium hydroxide and containing up to 1% glycerin. The dispersion was mixed in an orbital Ross mixer @1725 RPM for 5 minutes followed by mixing in an orbital Ross mixer @1725 RPM for 40 minutes while holding a vacuum @26 mm Hg or more. The composition was then steam sterilization at 121 degrees C. for times ranging from 3 minutes to 12 minutes. In addition, one sample was sterilized for time intervals between 3 minutes and 12 minutes @121 degree C. Results are shown in FIG. 13 where G′ represents the elastic modulus, G″ represents the viscous modulus and η the complex viscosity. The profile shows that G′ and G″ intersect at 0.914 Hz (5.7 rad/sec). Above this frequency, the composition exhibits non-Newtonian solution characteristics (tan δ<1.0). The addition of glycerin to sodium CMC gel in potassium phosphate significantly affects the rheology of the composition, changing it from a fundamentally Newtonian fluid to non-Newtonian fluid above a frequency of about 1.0.

EXAMPLE 14

Preparation of 2.9% Sodium CMC Gel in Potassium Phosphate Buffer and Glycerin.
Sodium carboxymethylcellulose was prepared in sterile 25 mM to 100 mM potassium phosphate buffer adjusted to a pH of from about 7.2 to about 8.0 using potassium hydroxide and containing up to 1% glycerin. The dispersion was mixed in an orbital Ross mixer @1725 RPM for 5 minutes followed by mixing in an orbital Ross mixer @1725 RPM for 40 minutes while holding a vacuum @26 mm Hg or more. The composition was then steam sterilization at 121 degrees C. for times ranging from 3 minutes to 12 minutes. In addition, one sample was sterilized for time intervals between 3 minutes and 12 minutes @121 degree C. Results are shown in FIG. 14 where G′ represents the elastic modulus, G″ represents the viscous modulus and η the complex viscosity. The profile shows that G′ and G″ intersect at 1.065 Hz (6.7 rad/sec). Above this frequency, the composition exhibits non-Newtonian solution characteristics (tan δ<1.0). The addition of glycerin to sodium CMC gel in potassium phosphate significantly affects the rheology of the composition, changing it from a fundamentally Newtonian fluid to a non-Newtonian fluid above a frequency of about 1.0.

EXAMPLE 15

1150 C Sintered Materials include the Following Materials and Process Conditions:
Materials of this exampled included implants having: 30% to 45% Media; 2.6% to 3.25% CMC; 0 to 15% glycerin; 0 mM to 100 mM PBS.
The CMC, buffer, glycerin and media were added together and mixed with a planetary mixer for 20 minutes to 3 hours under continuous and sustained vacuum. Materials were filled into 1 cc syringes, pouched in alumina foil and terminally steam sterilized @121 C for 15 min to 30 minutes.

The rheology evaluation was carried out on 30% and 40% media, 2.6% CMC to 3.25% CMC, 1.5% to 15% glycerin, 0 to 25 mM. The results of which are shown in FIGS. 15-19. The materials tested and some of their properties are listed in Table 2. The first column implant is that as taught in prior art. The second column implant is in accordance with the principles of the present invention for use in high mobility tissues. The third column implant is also in accordance with the principles of the present invention, but for usage in higher bulking required tissues situations where contour shaping and the filling is of principle concern.



	30% CaHA-	30% CaHA-	40% CaHA-
	3.25 CMC;	2.6% CMC;	2.6% CMC;
Physical parameters/	15%	1.5%	1.5%
Material composition	glycerin	glycerin	glycerin

Osmolality (mmol/kg)	1768 to 2300	291	289
Extrusion Force	6.1	5.4	4.8
(lbf, 0.5″ 27 Ga.)
Extrusion Force	11.5	9.8	7.6
(lbf, 1.25″ 27 Ga.)
Viscosity (η @ 0.5 Hz)	413750	202865	396585
Tan δ @ 0.5 Hz	0.453	0.595	0.581
Viscosity modulus	1478.60	678.32	1331.8
(G″@ 0.5 Hz)
Loss Modulus	671.69	404.30	773.23
(G′ @ 0.5 Hz)

FIG. 15 illustrates the viscosities for each of the materials as shear rate varies. FIG. 16 illustrates the loss modulus for each of the materials as sheer rate varies. FIG. 17 illustrates the viscosity modulus for each of the materials as sheer rate varies. FIG. 18 illustrates the δ for each of the materials as sheer rate varies.
Material is shear thinning. Varying the gel composition concentrations within the gel carrier, offers the potential to mimic other rheological variables at higher % particle medias. Degradation rates of the particles can be manipulated through formulation in gel rheology. The descriptive characteristics of viscosity and elasticity can be varied or maintained through gel composition concentrations. The lower viscosity modulus G″ and loss modulus G′ are similar in magnitude to physiological tissues studies and further asserts the improved biocompatibility not previously reported in prior art.
The time dependency of the elasticity is demonstrated in FIG. 19 for varying gel compositions with varying concentrations of particles. 30% & 40% solids in 2.6 CMC: 1.5% glycerin carrier vs. 30% solids in a 3.25% CMC: 15% glycerin carrier. The material demonstrates a time dependency to material break down due to composition. The material with less particles and lower viscosity gels have less tendency to withstand material stresses.

EXAMPLE 16

1150 C Sintered Materials Alginate: CMC Carrier and include the Following Constituents and Processes:
M087052: 30% Media, 40 mg/ml to 100 mg/ml alginate: 7.5 mg/ml to 12.5 mg/ml, 25 mM PBS, 1.5% glycerin
The following Alginate/CMC gel formulations (mg/mL) were prepared using the process detailed below:
The Alginate: CMC, buffer, glycerin were added together and mixed for 20 min to 3 hours. Particles were then added in 30% by volume and mixed for 20 min to 3 hours. Materials were filled into 1 cc syringes, pouched in alumina foil and terminally steam sterilized @ 121 C for 15 min to 30 mins.
Rheological evaluation for these materials are illustrated in the FIGS. 20 and 21. FIG. 20 illustrates the loss modulus G′, the elastic modulus G″ and tan δ (G′/G″). FIG. 21 illustrates viscosity and tan δ properties.

EXAMPLE 17

In one embodiment, the implant may be designed for application in the laryngeal tissue. Table 3 lists the parameters for such an implant.



	Specification	Laryngeal Implant

	Viscosity	107,620-517,590 cps.
	Osmolarity	255 mOs to 327 mOs
	pH	7.0 ± 1.0
	Loss on Drying	−29.7% to −43.1%.
	Percent Solids	54.3 to 70.5%
	Extrusion Force	3.60-7.20 lbsf

Although the present invention has been described with reference to preferred embodiments, one skilled in the art can easily ascertain its essential characteristics and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, various reasonable equivalents to the specific embodiments of the invention herein. Such equivalents are to be encompassed in the scope of the present invention. For example, the plasticizer utilized in the examples of the present invention is primarily glycerin. However, one of ordinary skill in the art would appreciate that other plasticizers may be used without departing from the spirit and scope of the invention.

Claims

1. A method of preparing an implant having viscoelastic mechanical properties selected to match tissue at a site of implantation, the method comprising:

preparing a polymeric polysaccharide in a buffer to create a polysaccharide polymer solution or gel;

preparing a plurality of ceramic particles, the ceramic particles having a size range of about 20 microns to about 200 microns;

suspending the plurality of ceramic particles in the polysaccharide gel forming an implant having a concentration of particles of about 5% to about 65%; by volume;

selecting a rheological profile for the implant, the rheological profile selection based on rheological properties of the tissue at the site of implantation; and

adjusting rheological properties of the implant to the selected rheology profile, wherein the implant exhibits similar biomechanical behavior as the tissue into which it is implanted.

2. The method of claim 1, wherein the polysaccharide polymer is selected from the group consisting of a cellulose polysaccharide and a hemicellulose polysaccharide.

3. The method of claim 1, wherein the polysaccharide polymer is selected from the group consisting of: sodium carboxymethylcellulose, hydroxyethyl cellulose, ethylhydroxyethyl cellulose, carboxymethyl cellulose, carboxyethylhydroxyethyl cellulose, hydroxypropylhydroxyethyl cellulose, methyl cellulose, methylhydroxylmethyl cellulose, methylhydroxyethyl cellulose, carboxymethylmethyl cellulose, and modified derivatives thereof.

4. The method of claim 1, wherein the adjusting of the ionic properties involves adjusting the pH of the solution to about 6.8 to about 8.0.

5. The method of claim 1, wherein the particles have a size range of about 20 to about 200 microns.

6. The method of claim 1, wherein the particles have a size range of about 20 to about 120 microns

7. The method of claim 1, wherein the particles have a size range of about 20 to about 45 microns

8. The method of claim 1, wherein the implant comprises about 5 to about 65% (by weight) of the particles

9. The method of claim 1, wherein the implant comprises about 10 to about 50% (by weight) of the particles

10. The method of claim 1, wherein the implant comprises about 30 to about 45% (by weight) of the particles

11. The method of claim 1, wherein the gel comprises about 0.1 to about 10% (by weight) CMC.

12. The method of claim 1, wherein the gel comprises about 1.5 to about 5% (by weight) CMC.

13. The method of claim 1, wherein the gel comprises about 0.1 to about 5% (by weight) of a plasticizer.

14. The method of claim 1, wherein the gel comprises a first polymer and a second polymer

15. The method of claim 1, wherein the first polymer and the second polymer may form crosslinks there between or act individually on the material performance.

16. The method of claim 1, wherein the implant has an osmolarity of between about 255 mOs and about 600 mOs.

17. The method of claim 1, wherein the implant has an osmolarity of between about 255 mOs and about 327 mOs.

18. The method of claim 1, wherein the implant has an osmolarity of between about 280 mOs and about 303 mOs.

19. The method of claim 1, wherein the implant comprises between about 57.9% to about 70.3% (by weight) of water.

20. The method of claim 1, wherein the tan δ of the implant is between about 0.5 to about 3.5.

21. The method of claim 1, wherein the tan δ of the implant is between about 0.5 to about 2.0

22. A composite material for tissue augmentation comprising:

a gel having suspended particles therein;

the injectable gel having a tan δ between about 0.5 and about 1 as measured at 0.65 Hz (3.8 rad/sec) and a osmolality of less than about 600 mOs.

23. An article implanted in a human, the article comprising:

a gel, the gel including carboxymethylcellulose in a concentration of 0.1% to 10% and having less than 5% by weight glycerin;

a plurality of particles, the particles being biocompatible and having a particle size of less than 200 microns;

the plurality of particles suspended in the gel such that the gel acts as a carrier for the particles;

the implant having predetermined biomechanical properties,

wherein the predetermined biomechanical properties of the implant in vivo are substantially similar to those of tissue into which the implant is injected.

24. The article of claim 23, wherein the tissue is lip tissue and further wherein the article provides a smooth, continuous flow into muscle and connective tissue surrounding the lip.

25. The article of claim 24, wherein the particles are substantially homogenously suspended and do not form concentrated pockets of particles when implanted.

26. The article of claim 24, wherein the gel comprises a range of biomechanical properties to match a range of those of the lip tissue.

27. A system for augmentation of tissue, the system comprising:

a syringe and a needle attached thereto;

an injectable implant, the injectable implant comprising a polysaccharide gel having suspended ceramic particles therein;

the polysaccharide gel comprising carboxymethylcellulose in a concentration of 0.1% to 10% and having less than 5% by weight glycerin;

the ceramic particles being biocompatible and having a particle size of less than 200 microns;

the injectable gel is shear thinning and having a viscoelastic profile, the viscoelastic profile having a viscosity modulus of between 100 mPas and 3000 mPas and and an elasticity modulus between 150 mPas and 2900 mPas,

the viscoelastic profile selected to substantially match that of the tissue,

wherein the injectable gel is extrudable through the needle forming a tissue augmentation implant that exhibits biomechanical properties similar to that of the tissue.

28. A biocompatible implant for a patient site comprising,

a particle mass; and

a biocompatible carrier for suspending the particle mass to be implanted into the patient site which has selected biochemical and biomechanical characteristic patient site properties and the biocompatible carrier having its characteristic biochemical and biomechanical properties matching the characteristic patient site properties such that the biocompatible implant remains mechanically stable at the site and has an exterior cosmetic appearance the same as the tissue site without cosmetic phase separation.

29. The biocompatible implant as defined in claim 28 wherein the biocompatible carrier includes a tan δ the same as the surrounding patient site.