KR20020043557A - Tissue Augmentation Material and Methods - Google Patents

Abstract

The present invention relates to permanent biomiscible materials for soft tissue augmentation. The biomiscible material comprises a matrix of particles of smooth, rounded, undifferentiated substantially spherical biomiscible ceramic material in close proximity or contact with each other and is capable of autogenous three-dimensional randomly oriented, scarlet soft tissue growth at the site of augmentation. Provide a skeleton or lattice for. Enhancers may be suspended homogeneously in biomiscible resorbable lubricity gel carriers comprising polysaccharides. This improves the injection and delivery of augmentation materials to tissue areas where augmentation is desired. The enhancing substance is particularly suitable for urethral sphincter augmentation, treatment of urinary incontinence, filling of soft tissue voids, production of soft tissue blisters, treatment of unilateral vocal cord paralysis and breast transplantation. The material may be intradermal, subcutaneous or implanted.

Description

Tissue Augmentation Material and Methods

Examples of biocompatible materials proposed to be used for soft tissue augmentation in cosmetic or reconstructive surgeries include beads of natural or synthetic polymers such as collagen, gelatin beads, polytetrafluoroethylene, silicone rubber, and polyacrylonitrile. Various hydrogel polymers such as polyacrylamide hydrogels.

In general, the biomaterial is delivered to a tissue site in need of augmentation by a biocompatible fluid and an injectable composition comprising the biomaterial that acts as a lubricant to enhance the injectability of the biomaterial suspension. Injectable biomaterial compositions may be introduced into a tissue site from a syringe by intradermal or subcutaneous injection in humans or other mammals to augment soft tissue, or to correct congenital abnormalities, acquired defects or cosmetic defects. Biomaterials may also be injected into such tissues to augment internal tissues, such as tissues that form the sphincter in the treatment of incontinence, and to treat unilateral vocal cord paralysis.

U.S. Patent Application No. 2,227,176 to Ersek et al. Describes physiological conditions suitable for predetermined sites such as the base of recessed scars, underneath recessed skin areas, and underneath cartilage or periosteum with irregular bone and cartilage surfaces in reconstructive surgery. A microtransplantation method for filling surface defects of recessed scars, asymmetrical orbital walls and bones using vehicle and subcutaneous needles and microparticles of about 20-3,000 μm injectable with a syringe. Textured microparticles can be used, including silicone, polytetrafluoroethylene, ceramic, or other intercalating materials. If hard materials are desired, biocompatible materials such as calcium salts, including hydroxyapatite or crystalline materials, biocompatible ceramics, biocompatible metals such as stainless steel particles, or glass can be used. Suitable physiological vehicles have been proposed, including saline, various starches, polysaccharides, and organic oils or fluids.

Wallace et al., US Pat. No. 4,803,075, relates to an injectable implant composition for augmenting soft tissue, comprising an aqueous suspension of particulate biocompatible natural or synthetic polymers and a lubricant that enhances the injectability of the biomaterial suspension. will be.

US Pat. No. 4,837,285 to Berg et al. Relates to collagen-based compositions for augmenting soft tissue repair, wherein the collagen is in the form of resorbable matrix beads having an average pore size of about 50 to 350 μm, the collagen being Account for less than about 10% of the volume of the beads.

US Pat. No. 4,280,954 to Yanas et al. Describes a collagen system for surgical use formed by contacting collagen with mucopolysaccharides under conditions in which collagen and mucopolysaccharides form a reaction product, which is then crosslinked by covalent bonds. It relates to a composition.

Lim, U.S. Pat.No. 4,352,883, discloses biotissues or individual cells by encapsulation of polysaccharide rubber that can be gelled to form shape bearing objects by exposure to changes such as pH changes or polyvalent cations such as calcium. A method of encapsulating a core material in form is disclosed.

Namiki, Namiki, "Application of Teflon Paste for Urinary Incontinence-Report of Two Cases", Urol. Int., Vol. 39, pp. 280-282 (1984) discloses the use of polytetrafluoroethylene paste in the subcutaneous area to treat urinary incontinence.

Drobeck et al., "Histologic Observation of Soft Tissue Responses to Implanted, Multifaceted Particles and Discs of Hydroxylapatite", Journal of Oral Maxillofacial Surgery, Vol. 42, pp. 143-149 (1984) disclose the effect on the soft tissues of long-term and short-term transplants of ceramic hydroxylapatite implanted subcutaneously in mice and subcutaneously and periosteally in dogs. The present invention consists in implanting hydroxylapatite of various sizes and shapes for various periods of 7 to 6 years to determine whether migration and / or inflammation is present.

Misiek et al., "Miniek et al.," Soft Tissue Responses to Hydroxylapatite particles of Different Shapes ", Journal of Oral Maxillofacial Surgery, Vol. 42, pp. 150-160 (1984) disclose that hydroxylapatite implantation in the form of sharp edged or rounded edges in the oral soft tissue sac produced an inflammatory response at the site of implantation in both particle types. The weight of each particle was 0.5 g. However, the inflammation disappeared at a faster rate at sites implanted with rounded hydroxyapatite particles.

Shimizu et al., Simizu, "Subcutaneous Tissue Response in Rats to Injection of Fine Particles of synthetic Hydroxyapatite Ceramic", Biomedical Research, Vol. 9, No. 2, pp. 95-111 (1988) discloses that phagocytosis is caused by macrophages in very early stages when subcutaneous injection of microparticles of hydroxyapatite with a diameter of about 0.65 to several μm is scattered into tissues. In contrast, phagocytosis did not occur for large particles of several micrometers in diameter, but was surrounded by a myriad of macrophages and multinuclear giant cells. It has also been observed that the response of small tissues to hydroxyapatite particles is essentially a nonspecific response to foreign objects without any damage to cells or tissues.

Apel, R. A. Appell, "The Artificial Urinary Sphincter and Periurethral Injections", Obstetrics and Gynecology Report Retort Vol. 2, No. 3, pp. 334-342 (1990)] treat urethral sphincter dysfunction, including the use of injectables, such as polytetrafluoroethylene micropolymer particles of amorphous size of about 4 to 100 μm, with glycerin and polysorbate. It relates to a measurement article that discloses various methods. Another method injectable around the urethra consists of highly purified bovine skin collagen that is crosslinked with glutaraldehyde and dispersed in phosphate-buffered saline.

Politano et al., "Periurethral Teflon Injection for Urinary Incontinence", The Journal of Urology. Vol. 111, pp. 180-183 (1974) disclose the use of polytetrafluoroethylene paste injected into tissues to restore urinary incontinence control by applying bulk to the urethra and periurethral tissue in female and male patients suffering from urinary incontinence. .

See, eg, Malizia et al, "Migration and Granulomatous Reaction After Periurethral Injection of Polytef (Teflon)," Journal of the American Medical Association, Vol. 251, No. 24, pp. 3277-3281, June 22-29 (1984)], although in patients with urinary incontinence were successfully treated by injecting polytetrafluoroethylene paste around the urethra, studies in incontinence animals showed that polytetrafluoroethylene particles were moved from the site of irradiation. Proved.

Claes et al, "Pulmonary Migration Following Periurethral Polytetrafluoroethylene Injection for Urinary Incontinence", The Journal of Urology, Vol. 142, pp. 821-22, (September 1989), confirmed the finding of Malaria by reporting a clinically significant case of polytetrafluoroethylene paste migration to the lungs after periuretic injection.

Ersek et al, "Bioplastique: A New Textured Copolymer Microparticle Promises Permanence in Soft-Tissue Augmentation", Plastic and Reconstructive Surgery, Vol. 87, No. 4, pp. 693-702, (April 1991), was made of fully polymerized and vulcanized methylmethylpolysiloxane mixed with plasmon hydrogel, which contained cleft lip, recessed scars of chickenpox, and liposuction, frown wrinkles and Disclosed is the use of a biphasic copolymer used to rebuild indentation resulting from soft tissue augmentation of thin lips. The ideal copolymer particles do not migrate or are absorbed by the body, have a feel, and have a particle size of 100 to 600 µm.

Lemperle et al., Lemperle et al., "PMMA Microspheres for Intradermal Implantation: Part I. Animal Research", Annals of Plastic Surgery, Vol. 26, No. 1, pp. 57-63, (1991) disclose the use of polymethylmethacrylate microspheres for the treatment of wrinkles and acne scars by correcting small defects in the skin dermis with a particle diameter of 10 to 63 μm.

Cressa et al., Hydraron Gel Implants in Vocal Cords, Otolaryngology Head and Neck Surgery, Vol. 98. 3, pp. 242-245, (March 1988), for the treatment of diseases in which the vocal cords are adjusted without sufficient closure of the vocal cords, including the introduction of a molded implant of hydrophilic gel, previously dried in a glassy solid state, into the vocal cords. A method is disclosed.

Hirano et al., Transcutaneous Intrafold Injection for Unilateral Vocal Cord Paralysis: Functional Results, Ann. Otol. Rhinol. Laryngol., Vol. 99, pp. 598-604 (1990) discloses a percutaneous intrafold silicone injection technique used for the treatment of glottal dysfunction caused by unilateral vocal cord wrinkle paralysis. Silicone injection is performed by local anesthesia with the patient lying flat so that the needle is inserted through the cricothyroid space.

Hill et al., “Autologous Fat Injection for Vocal Cord Medialization in the Canine Larynx”, Laryngoscope, Vol. 101, pp. 344-348 (April 1991) consider Teflon (TM) collagen as an implantable substance in medialization of vocal cords, taking into account the use of autograft fats to replace non-autografts in vocal cords. The use of implantable fats is disclosed.

Michaelian et al., Mikaelian et al, "Lipoinjection for Unilateral Vocal Cord Paralysis", Laryngoscope, Vol. 101, pp. 4654-68 (May 1991) describes a commonly used method of injecting Teflon (R) paste to improve the quality of speech in the treatment of unilateral vocal cord paralysis from overinjected Teflon (R). Have many defects, including respiratory distress and unsatisfactory voice quality. In this method, lipid injection of fat, commonly found in the abdominal wall, seems to distribute bulky soft tissue to the injected vocal cords while allowing the vocal cords to retain their quality of vibration. Injected fat is an autograft that can be recovered in case of overinjection.

Strasnick et al., Strasnick et al, "Transcutaneous Teflon Injection for Unilateral Vocal Cord Paralysis: An Update", Laryngoscope, Vol. 101, pp. 785-787 (July 1991) discloses a Teflon® injection method for restoring the ability of the gates in the case of paralytic speech disorders.

<Overview of invention>

In accordance with the present invention, a permanent biocompatible material for soft tissue augmentation and a method for using the same is provided. Also provided in accordance with the invention are gel carriers which are particularly advantageous for administering biocompatible materials to desired tissue enhancement sites.

Biocompatible materials are soft, rounded, substantially spherical, particles of finely divided biocompatible ceramic material that are in close proximity or contact with each other, resulting in endogenous, three-dimensional, randomly oriented, scar-free soft tissue growth at the augmentation site. A matrix forming a scaffold or grating for the purpose. Enhancers may be uniformly suspended, for example, in biocompatible and resorbable lubricity gel carriers (eg, polysaccharides). This acts to enhance the delivery of the augmenting substance by injection to the site of tissue in need of augmentation. Augmenting agents are particularly suitable for urethral sphincter augmentation, particularly for treating incontinence, filling soft tissue voids, creating soft tissue blisters, treating unilateral vocal cord paralysis, and implanting breasts. Enhancers may be injected or implanted intradermal or subcutaneously.

The present invention provides a biocompatible composition for soft tissue augmentation, more specifically for increasing urethral sphincter for incontinence treatment, to fill soft tissue space or to produce soft tissue blisters, for breast transplantation, and unilateral vocal cord paralysis. It relates to a biocompatible composition for treatment. The present invention also relates to gel carriers for biocompatible compositions.

In the accompanying drawings,

1 is an optical microscope photograph of a smooth, round-shaped calcium hydroxyapatite particle at 40 times magnification;

FIG. 2 shows fibroblastic infiltration with micrographs at 50-fold magnification of histological sections of rabbit tissue; FIG.

3 is a graph showing the viscosity of gel and enrichment medium before and after sterilization.

In urinary incontinence, such as stress incontinence in women or incontinence after men's prostatectomy, the urethra must be closed to help close the sphincter and prevent urine leakage from the bladder.

The soft tissue enhancing substances of the present invention can be used to add bulk and include an injection system that can concentrate pressure on the sphincter / urethra, thereby reducing lumen size by injecting the enhancement substance one or more times. Thereby reducing or eliminating stress incontinence due to dysfunctional sphincter in men and women.

Augmenting materials can also be used to fill and remove soft tissue defects such as spot marks or scars. The use of augmentation material may also be for vocal cord injection of the laryngeal vocal cord to change the shape of the soft tissue masses of the vocal cords. The process involves the delivery of an augmentation substance to the treatment site, preferably by injection. Enhancers or gels can also be used for breast transplantation.

Augmentation materials of the present invention comprise smooth, circular, substantially spherical ceramic material particles. The term "substantially spherical" means that some of the particles may be spherical, but most of the particles of the invention are spherical in shape, i.e., spheroids. 1 is a schematic diagram of these spheroids or substantially spherical properties. As used herein, the term "circular" or "smooth, circular" means that the particles are not completely spherical but have no sharp or angled edges. As discussed further below, the particles should be large enough to avoid phagocytosis. As an upper limit, the particles can be of any size suitable for the purpose of soft tissue enhancing material. However, it is understood that the upper limit of particle for injection by injection will be specified by the specific injection device used. That is, the particles must be small enough to agglomerate and avoid clogging the syringe when injected. Typical ranges for injection are about 35 to 150 microns, preferably within a narrow particle size range spanning less than about 35 microns, more preferably within a particle size range spanning less than about 10 to 30 microns, and substantially the same. Most preferably it has a particle size. For example, the ceramic material may have a uniform particle size distribution of about 35 to 65 microns, or 75 to 100 microns but 100 to 125 microns. This is for illustrative purposes, not limitation. Other narrow particle size ranges, which are generally within the size range of 35 to 150 microns, may be used. In discussing these ranges, it is to be understood that, as a practical matter, a small amount of particles outside the preferred ranges may be present in the sample of this enhancement material. However, most of the particles in a given sample should be within the desired range. Preferably 90% of the particles are in the desired range, most preferably 95 to 99% are in that range.

Precisionly divided ceramic enhancement materials are substantially non-degradable and do not require repeated calibration. "Substantially non-degradable" means that over time some degradation of the augmentation material may occur but it is slow enough to be replaced by growing tissue cells. There is no antigen response because there is no amino acid as in collagen and fibrinogen. Ceramic materials are highly biocompatible and can be injected through open syringes of up to 18 gauge.

Preferred ceramic materials are calcium hydroxyapatite (hydroxyapatite) or calcium hydroxyapatite (hydroxyapatite), also known as basic phosphate calcium, which is the natural mineral phase of teeth and bones. As a graft material, granular calcium hydroxyapatite, a sintered polycrystalline composite of calcium phosphate, has proven to be highly compatible in tissues.

One method for producing high density, circular or substantially spherical ceramic particles, such as calcium hydroxyapatite, is spray drying a slurry of about 20 to 40% by weight of calcium hydroxyapatite having a particle size of less than micron units. This material is commercially available or can be prepared by known methods such as low temperature crystallization methods, hydrothermal crystallization methods, solid-solid reactions and the like. The slurry may also contain about 1 to 5 percent by weight of processing additives such as wetting agents and binders. Suitable wetting agents include polysorbates, sodium oxalate, ammonium polyelectrolytes. Suitable binders include polyvinyl alcohol, dextrin or carbowax.

The slurry is sprayed through a nozzle to form globules, which are spray dried by passing through heated air columns to remove moisture. The aggregated particles are collected at one end of the substantially spherical dried and heated air column.

Subsequently, the substantially spherical particles are sintered for at least 1 hour at harsh temperatures of about 1050 to 1200 ° C. To minimize further agglomeration, presintering can be performed at about 800 to 1000 ° C. for about 1 hour.

After the pre-sintering operation, the globule particles may be stirred or rolled to prevent the individual particles from sticking together or clumping together. Rotary kilns can be used for this purpose. This type of furnace rotates to cause the flocculated particles to oscillate against each other during the sintering process, thereby minimizing the flocculation of the particles together. The product source for such spray dried particles is CeraMed Corp., Lakewood, Colorado.

An alternative to the formation of high density, spherical particles is by rotary agglomeration, in which refined ceramic particles, such as calcium hydroxyapatite, are placed in a large diameter rotating bowl of at least about 3 feet (0.91440 meters) in diameter.

The bowl rotates at an angle of about 30 degrees on the axis, the rotational speed and angle of which is adjusted so that particles smaller than microns are oscillated along the bowl's surface. Thereafter, fine spraying of the binder solution as described above is ejected onto the particles at a rate such that the particles only get wet. The rocking motion to roll on the bowl's surface and the addition of binder solution cause the particles to form small rock aggregates that grow in size as the operation continues. This task is comparable to forming a large snowball by rolling a small snowball down the hill. Operating conditions such as the size of the bowl, the speed of rotation, the angle of rotation and the amount of spray used are well known to those skilled in the art, which determine the size and density of the aggregates formed. The agglomerated spherical particles may then be sintered in a similar manner as the spray dried agglomerates.

The resulting sintered spherical particles can then be separated and classified by size in the manner of well known sieving operations through a mesh screen of a particular size. Particle size distributions and densities can also be evaluated for suitability for particular applications. The commodity source for such agglomerated particles is CAM Implants, Leiden, The Netherlands.

In addition, surface refining or smoothing can be performed by milling operations such as ball milling. Excess mini-grinding media can be used, but milling with only spherical particles can be used to minimize contamination. This can be done by adding a sufficient amount of purified water to the particles in a standard jar mill or oblique rotating mill to allow the particles to swing evenly with each other. This can be done for a long period of time, for example several days, so that the circular aggregate surface is smooth. If the starting aggregate is not circular, it may be smooth but not circular by oscillation. Irregularly shaped agglomerates, even with smooth surfaces, can clog when injected into tissue, interfere with the injection or significantly increase the injection pressure on the needle.

Aggregated spherical particles can also be washed to eliminate small particles using an inclined rotary mill. This can be done by putting the agglomerates into the mill with purified water and shaking for a sufficient time, for example 1 hour. Thereafter, the supernatant is discarded and further purified water is added. The process is repeated until the supernatant is relatively clear after the cycle of rotation, which usually requires about three to four operations.

The method described above is suitable for any ceramic material that can be used.

Smooth surfaces on individual circular, spherical particles are important for reducing and minimizing surface porosity. Smooth surfaces can be obtained by finishing operations known in the art such as surface milling and the like. Such a finishing operation is preferably capable of minimizing surface irregularities on individual particles such that a smooth circular bead-like surface appears upon viewing under a 40x microscope. This is evident in FIG. 1 (optical micrograph of calcium hydroxyapatite particles with a particle distribution of 38 to 63 microns). A smooth, circular, substantially spherical, non-porous surface is immediately revealed.

The ceramic particles are preferably smooth, hard, circular particles whose density is about 75 to 100%, preferably about 95 to 100% of the calculated density of the desired ceramic material, for example calcium hydroxyapatite. The finishing operation can also minimize the surface porosity of the calcium hydroxyapatite particles to less than about 30%, preferably less than about 10%. Finishing operations are desirable because minimizing surface porosity results in particles with smooth surfaces, thereby eliminating uneven and irregular surfaces and maximizing the ability for smooth, circular particles to flow easily in contact with each other. .

Although the present invention has been described by calcium hydroxyapatite, other suitable materials useful herein include, but are not limited to, calcium phosphate based materials, alumina based materials, and the like. Examples include, but are not limited to, tetracalcium phosphate particles, calcium pyrophosphate particles, tricalcium phosphate particles, octacalcium phosphate particles, calcium fluoroapatite particles, calcium carbonate apatite and combinations thereof. Other calcium-based compositions equivalent to those of calcium carbonate may also be used.

As mentioned, the individual ceramic particles used in the present invention are generally smooth, circular, and preferably spherical, in contrast to particles having a rougher porous surface or perforated and uneven, irregular surface or straight angle. . The smooth circle allows the ceramic particles to be more easily injected and flow with reduced resistance from the syringe to the tissue site where soft tissue enhancing material is needed. Once at the tissue site, the ceramic particles provide a matrix or framework for endogenous tissue growth.

As mentioned above, the particle size in the range of about 35 to 150 microns is optimized to minimize the possibility of particle migration by phagocytosis and to facilitate injection ability. Phagocytosis occurs where smaller particles, on the order of 15 microns or less, are captured by the cells and where the augmenting substance is removed by the leukocyte system from the site injected, usually by injection.

At the lower limit, particles larger than 15 microns and typically at least 35 microns are too large for phagocytosis to occur and can be easily separated by known sizing techniques. Thus, it is relatively simple to produce in a narrow particle range or most preferably the same particle size range for the use of the present invention.

In addition, the distribution of such smooth, circular, substantially spherical particles reduces the resistance and facilitates the injection of the particles by the needle into the skin tissue at the site of enhancement. Preference is given to using ceramic particles in the size range. This is in contrast to using more porous, coarse and irregularly shaped particles that increase resistance and are more difficult to deliver by injection.

As discussed above, it is desirable to minimize the particle size distribution or range of particle sizes of the ceramic material to be within a narrower range or to have the same particle size range overall within 35 to 150 microns. This maximizes the void volume or interstitial volume where the endogenous tissue growth stimulated by the presence of augmentation material can occur. Compared to particles with varying size distributions, there is a larger gap volume between particles of the same size. For the purposes of the present invention, a gap volume is a void present between particles of augmentation material that are close or in contact with each other.

For example, in crystal lattice structures such as face-centered cubic, body-centered cubic and simple cubic structures, the percentage of gaps known as atomic filling rates are 26%, 33% and 48%, respectively. It is independent of the diameter of the atom or, in this case, of the particle. Since the ceramic particles are not densely packed like atoms in the crystal lattice structure, the void volume is larger, thereby maximizing endogenous tissue growth. Expanding the comparison with the crystal structure one step further, the interstitial space determines the maximum size that the particles can fit into the voids that normally appear within the structure. The largest gap space is about 0.4 times the average ceramic particle size in the particle size distribution.

That is, if the particle size distribution is about 35 to 65 microns, the average particle size will be 50 microns. The largest lattice spacing would be 50 x 0.4 = 20 microns. There is no particle size of 20 microns in the distribution, so filling will be minimized. Likewise, for a particle size distribution of 75 to 125 microns, the average particle size would be 100 microns and the largest lattice spacing would be 100 x 0.4 = 40 microns. There will be no 40 micron particles in the distribution so the filling will also be minimized. Thus, if the ceramic particles are limited to a narrow particle size range or the same size distribution, the void volume from which the native tissue can grow will be maximized.

Other suitable particle size distribution ranges are 35 to 40 microns, 62 to 74 microns and 125 to 149 microns, but any other correspondingly narrow range may also be used.

In contrast, in the case of a wide particle size distribution, the smaller particles tend to move or flock at intervals between the larger particles, so the particles tend to be densely packed. This results in less lattice spacing available between particles for infiltrating and growing native tissues such as fibroblasts and chondrocytes.

Tissue growth in which the augmentation material has a wide particle size distribution is denser and harder due to the filling effect occurring between large and small particles. Conversely, the use of particles having a narrow particle size distribution of particles of the same size or evenly distributed increases the pore volume in the particles. This allows autogenous or three-dimensional randomly oriented non-scar soft tissue to infiltrate the spacing or lattice between the particles at maximum in growth. The more lattice spacing available, the more likely will be the continuous autologous tissue growth promoted by the presence of the augmentation material into the matrix or scaffold material provided by the augmentation material, similar to the original tissue in the immediate vicinity or place of the increase.

The soft tissue extension method may be caused by the formation of small bubbles or blisters by injection or implantation of a biocompatible enhancement material comprising the desired particle size of the desired ceramic material into the tissue at the desired extension site. Continuous autologous tissue growth into the matrix provided by this enhancer will be most closely similar to the enclosed tissue in structure and properties. This is in contrast to using known methods in the art, using Teflon (R) increments, which are known to cause foreign body reactions, typically granulomas are known.

A foreign body reaction is a biological reaction to a foreign body. A representative foreign tissue response is the appearance of polymorphonuclear leukocytes around the material after macrophages, followed by macrophages. If the material is non-bioreactive, such as silicone, only thin collagen encapsulated tissue is formed. If the substance is irritating, inflammation will occur, which will ultimately lead to granulation tissue formation. Ceramic materials such as calcium hydroxyapatite are excellent in biocompatibility, causing tissue cell growth directly on the surface of the particles with minimal or substantially no encapsulation.

Autologous tissue is defined herein as any tissue at a particular location in the body where its growth is facilitated by the presence of a matrix of biocompatible enhancing substances at the site where soft tissue enlargement is desired. For example, an autologous tissue caused by an increase in the area of the urethral sphincter may be similar to an existing tissue of the urethral sphincter. The autogenous organization of the larynx may be similar to the existence of the vocal cords where the larynx vocal cords are located. Autologous tissue from breast augmentation will be similar to existing tissues such as breast. For intradermal injection, the autologous tissue will be similar to the dermis. In a similar manner, by providing a three-dimensional grating, the augmentation material can be used for surgical incisions or injuries to avoid linear layered contractile wound formation.

As noted above, the calcium hydroxyapatite particles used as enhancing materials are biocompatible and substantially non-resorbable. Thus, the soft tissue expansion procedure is permanent. In addition, the use of calcium hydroxyapatite does not require rigorous precautions where storage, loading and antigenicity testing are essential when using other enrichment materials such as collagen that require refrigeration.

Round, spherical smooth calcium hydroxyapatite particles enhance biocompatibility for autologous tissue reactions into the particle matrix and substantially eliminate the possibility of calcification. Jagged or irregular particles can irritate tissue and cause calcification. In addition, surface porosity of at least about 30% by volume can also cause calcification because the pores in the particles are relatively stable. Smooth, rounded, substantially nonporous particles retain their movement in tissue. In other words, autogenous tissue grown in the particle matrix in which motion is maintained is not calcified. In contrast, the porous area of the individual particles is static relative to the particles, so that tissue infiltration into the pores does not move and calcification may occur.

Granular ceramic materials can be suspended in biocompatible and resorbable lubricants such as polysaccharide gels to improve the transport of enhancement material by injection to tissue sites where increase is required. Suitable polysaccharides will be apparent to those skilled in the art. Examples of the polysaccharides that can be used in the present invention include, for example, cellulose / starch, chitin and chitosan, hyaluronic acid, hydrophobic denaturation system, alginate, carrageenan, agar, agarose, intramolecular complex, oligosaccharide, and macrocyclic polysaccharide. There are any suitable polysaccharides in the class. Examples of polysaccharides that can be classified into four basic categories include: 1. Nonionic polysaccharides such as cellulose derivatives, starch, guar, chitin, agarose and dextron; 2. anionic polysaccharides such as cellulose derivatives, starch derivatives, carrageenan, alginic acid, carboxymethyl chitin / chitosan, hyaluronic acid and xanthan; 3. Cationic polysaccharides such as cellulose derivatives, starch derivatives, guar derivatives, chitosan and chitosan derivatives (including chitosan lactate); And 4. hydrophobic modified polysaccharides such as cellulose derivatives and alpha-emulic acid. 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.

Cellulose polysaccharide gels are particularly advantageous because of their so-called viscoelastic properties. Among these properties, there is a property of shear thinning. That is, the cellulose polysaccharide gel will flow more easily when applying force. This facilitates mixing when solid granules are added to the gel. Shear thinning also allows for easier transport of viscous material than otherwise. Another property of this material is elasticity, which tends to recover its initial form after denaturation. This is very important because the gel's elasticity allows the gel to suspend substantially indefinitely the enhancement material to achieve a substantially indefinite period of time. Relatively dense material can be suspended by this gel. For example, spherical hydroxylapatite granules ranging in diameter from 75 to 125 microns and density 3.10 g / cc can be suspended in a gel having a composition of 14.53 parts of glycerin, 82.32 parts of water and 3.15 parts of NaCMC.

The elastic properties of the gels according to the invention are further advantageous because the tissue enhancing substances and cellulose polysaccharide gels can be mixed using conventional mixing devices without backshocking the gel carrier so that the tissue enhancing substances can be suspended in the gel. That is, the gel carrier will not break or lose its elastic properties. These methods are enhanced by the rate of recovery of the gel elastic properties that occur once the hydrated gel is formed. This rapid form recovery due to elasticity is also very important for the placement and maintenance of the material when implanted in living tissue. The recovery of more viscous properties, once the dead power is removed, aids maintenance instead of the material to minimize exudation.

Any solvent suitable for the cellulose polysaccharide gel can be used in the present invention. For example, the gel can be an aqueous cellulose polysaccharide gel. Alternatively, the solvent may be an aqueous alcohol such as glycerol, isopropyl alcohol, ethanol and ethylene glycol, or mixtures thereof. Other solvents suitable for the gel carrier will be apparent to those skilled in the art. Surfactants, stabilizers, pH buffers and other additives that are apparent to those skilled in the art are also useful. Pharmaceutically active agents such as growth factors, antibiotics, analgesics and the like can also be usefully incorporated and will be apparent to those skilled in the art.

Also described herein are ceramic tissue enhancing materials, but the cellulose polysaccharide gel carrier of the present invention may be used as a carrier for other tissue enhancing materials. For example, the cellulose polysaccharide gel carrier of the present invention can be used as a carrier for non-ceramic tissue enhancing materials such as glass, polymethylmethacrylate, silicon, titanium and other metals, and the like. Other suitable non-ceramic tissue enhancing materials that can be suspended using the carrier of the present invention will be apparent to those skilled in the art.

The formation of the gel depends on a number of factors, such as 1) the molecular weight, degree of substitution and other properties of the polysaccharide, 2) the solvent system used, and 3) the final properties required for the particular application of the enhancing material. Generally, the ratio of cellulose polysaccharides to solvents may range from about 0.5 to 10: 95.5 to 90. For example, for the 85:15 water: glycerine mixture, the ratio is preferably about 1.5 to 5: 98.5 to 95, most preferably about 2.5 to 3.5: 97.5 to 96.5.

Preferably the gel comprises water, glycerin and sodium carboxymethylcellulose. The gel allows the ceramic particles to remain suspended between inorganics in which they are used, more specifically, without settling for at least about six months. Other suitable lubricating compositions known in the art can also be used.

In general, the ratio of water (or other solvent, such as saline, Ringer's solution, etc.) to glycerin in the gel is about 10 to 100: 90 to 0, preferably about 20 to 90:80 to 10, most preferably Preferably in the range of about 85:15.

The viscosity of the gel is from about 20,000 to about 350,000 centipoise, preferably from about 150,000 to about 250,000 centipoise, more preferably greater than 200,000 to about 250,000, measured at 16 rpm at 25 ° C. with a Brookfield viscometer with a RU # 7 spindle. It may be in the range of centipoise. Gel viscosities of less than about 20,000 centipoise have not been shown to cause particles to remain suspended, and gel viscosities greater than about 350,000 centipoise have been found to be too viscous for easy mixing.

In a preferred embodiment of the invention wherein the polysaccharide is sodium carboxymethylcellulose, the sodium carboxymethylcellulose contained in the gel has a high viscosity. More specifically, sodium carboxymethylcellulose is described in Hercules / Agualon Division Brochure 250-10F EV. 7-95 2M, "Sodium Carboxymethylcellulose Physical and Chemical Properties," pp. 26-27, it is preferred to have a viscosity of about 1000 to 4000 centipoise, preferably about 2000 to 3000 centipoise, in a 1% aqueous solution. The carboxymethylcellulose content may range from about 0.25 to 5% by weight, preferably 2.50 to 3.50% by weight of water (85 parts) and glycerin (15 parts) mixed in the gel.

The cellulose polysaccharide gel carrier of the present invention has been discussed in connection with the preferred sodium carboxymethylcellulose gel carrier. However, as mentioned above, any suitable polysaccharide gel may be used as a carrier according to the present invention, as long as any suitable polysaccharide gel uniformly suspends the tissue enhancing material for a substantially infinite period of time and possesses the shear thinning and elasticity described above. Can be useful. More specifically, the polysaccharide gel carrier preferably has the following shear thinning and elasticity. 1) a viscosity of 300,000 to 1,000,000 cps when a shear stress of 200 Pascal is applied and a shear stress of 1 to 5,000,000 centipoise and 500 Pa; 2) modulus of elasticity 50-1000 Pa under a maximum force of 100 Pa measured at 1 hertz; 3) ratio of viscosity coefficient to modulus of elasticity from 0.2 to 1.0 as measured under a maximum force of 100 Pa at 1 hertz; 4) 5 to 75% strain recovery after exposure to 100 Pa strain force for 120 seconds; And 5) most of the strain recovery in (4) occurs within 2 to 10 seconds. The measurement can be performed with a Haeake RS100 with a controlled stress flow meter, for example 2 cm parallel plates operated in stress ramp, vibration and creep / recovery modes. The actual values of shear thinning and elasticity described above will depend on the desired application and properties of the dispersed particulates (eg, size, density, etc.).

In the tissue enhancing materials and methods of the present invention, with cellulose, agar methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, microcrystalline cellulose, oxidized cellulose, chitin, chitosan, alginic acid, sodium alginate, xanthan gum and other equivalents Such other polysaccharides may also be included or used separately.

Unexpectedly, it is believed that the formulation of the augmentation material particles of the present invention, in particular the formulation of calcium hydroxyapatite with sodium carboxymethylcellulose, changes the surface morphology of the particles to enhance the physical properties and biocompatibility of the material.

Glycerin in preferred formulations provides several advantages. First, the composition is more slippery when glycerin is present. Second, when the polysaccharide gel forming material is in a predetermined amount, the viscosity is substantially enhanced in the presence of some glycerin compared to the pure aqueous gel. Third, the presence of glycerin minimizes water loss of the gel due to dehydration.

Gels are prepared by mixing gel components at ambient conditions until all components are in solution. It is preferred to first combine the glycerin and NaCMC components together until a thoroughly mixed solution is obtained. The glycerin / NaCMC solution is then mixed with water to form a gel until all components are in solution. After the gel components have been thoroughly mixed, the gel is left for at least 4 hours and then the viscosity values are taken so that the gel is at the desired viscosity.

While any lubricant or carrier can be used, certain materials, such as polysorbate surfactants, pectin, chondroitin sulfate and gelatin, cannot suspend ceramic particles for an indefinite period of time and in the same manner as the preferred sodium carboxymethylcellulose. It was found that it could not be further processed or easily injected into the furnace. Thus, sodium carboxymethylcellulose material is preferred.

Preferred polysaccharide gels are capable of retaining particles of ceramic material which are biocompatible and which result in a substantially permanent suspension so that ceramic particulate / gel compositions comprising augmentation material do not need to be mixed prior to use. As already mentioned, the lubricating properties of polysaccharide gels reduce the frictional forces that occur when delivery of augmenting substance from the syringe to the tissue site by injection.

In addition, polysaccharides do not generate antigen response like amino acid containing products. Polysaccharide gels can be easily sterilized at ambient conditions and are stable and do not need to be frozen for storage and transportation, in contrast to systems in which collagen-containing materials are used.

Sterilization is typically accomplished by pressurizing at a temperature of about 115 ° C to 130 ° C, preferably about 120 ° C to 125 ° C for about 30 minutes to 1 hour. Gamma rays are not suitable for sterilization because they can destroy the gel. In addition, the inventors have found that sterilization generally causes a drop in viscosity. However, as long as the viscosity of the gel is maintained in the above viscosity range, sterilization does not adversely affect the extruding force of the augmentation material through the suspension and syringe or the ability of the gel to retain calcium hydroxyapatite particles in the suspension.

After the augmentation agent is injected into the tissue, the polysaccharide gel is reabsorbed harmlessly to the tissue, and the non-reabsorbed calcium hydroxyapatite matrix remains in place in certain or round areas and does not migrate to other areas of the body. Found. In general, it takes about two weeks for polysaccharides to be completely resorbed.

FIG. 2 shows ten tissues of a 50-fold magnified rabbit infiltrated with randomly oriented, spontaneous three-dimensional intact soft muscle tissue as a result of injection of calcium hydroxyapatite particles with a uniform particle size of 38 to 63 microns. Indicates a tissue incision. The micrograph shows growth after 12 weeks. Tissue incisions also demonstrate the biocompatibility of calcium hydroxyapatite by growing cells on the surface of the particles with minimal or substantially no foreign body response.

The inventors have found that the amount of calcium hydroxyapatite particles in the enhancement material is from about 15% to 50% by volume, preferably from about 25% to 47.5% by volume, most preferably of the total enhancement material comprising gel and ceramic particles. It has been found that it can vary from about 35% to 45% by volume.

Formulations with more than 50% by volume of ceramic particles are viscous and care should be taken in the selection of the injection device. As a lower limit, the augmentation material of the present invention must clearly contain a sufficient volume of ceramic particles to provide an effective base for spontaneous tissue growth. In most applications, it is at least 15% by volume. By maintaining the volume percentage at about 35-45%, a correction factor of about 1: 1 can be achieved. That is, the volume of spontaneous growth of the tissue is approximately equal to the volume of particles introduced and no contraction or expansion generally occurs at the site of soft tissue enlargement.

Also within these parameters, the augmentation material can be easily injected intradermally or subcutaneously through an 18 gauge or less syringe. Because of the reduced frictional force required to deliver the biocompatible enhancing material to the desired tissue site by injection, the size of the syringe used to deliver or inject the biocompatible enhancing material can be significantly reduced. This substantially eliminates the possibility that needle marks can be created that can cause the augmentation material to leak from the injection site after withdrawing the injection needle. Thus, the syringe used to inject the enhancement material may have a hole reduced to less than 1,000 microns in diameter to about 178 microns or less.

For example, an 18 gauge syringe with a diameter of about 838 microns or a 20 gauge syringe with a diameter of about 584 microns or a 22 gauge syringe with a diameter of about 406 microns and even a 28 gauge syringe with a diameter of about 178 microns can be used. It depends on the tissue site in need of the increase.

The lubricious suspension of the enhancement material is prepared by simply mixing the desired amount of ceramic particles with the lubricious gel until a homogeneous homogeneous suspension is obtained. The consistency of the ceramic particles suspended in the lubricity gel is similar to strawberry jam, and for all practical purposes the seeds and other solids of the strawberry are similar to the ceramic particles and are substantially permanently suspended in the jelly jam matrix.

Suspensions of ceramic material in lubricious gels are stable such that centrifugal forces of about 500 g, ie, 500 times gravity, generally do not affect the stability of the suspension or settle the suspension. Even if present, the tendency to settle the particles for a period of time will be greater at larger particle sizes on the order of 125 microns or more. Thus, it is not usually necessary to remix the reinforcement at the time of infusion or implantation. In addition, since the polysaccharide gel smoothes the suspended ceramic particles, the injection force on the syringe can be minimized when injecting augmentation material.

The tissue enhancing substances according to the invention are particularly advantageous for the treatment of osteoporosis or related pathological treatments, for example for treating femoral or bone defects by trauma or surgical incisions. The advantages of these materials in these applications include biocompatibility, easy applicability, and good results when compared to other materials currently used.

In particular, because the material can be injected through a fine catheter and needle, small incision sites, such as holes less than 4.5 mm at the bone site, can be used, minimizing direct loss of the bone column. That is, the opposite of a longer period than intended. Because of the smaller needles required to use tissue enhancing materials in accordance with the present invention, the pore diameter can be greatly reduced and the depth can also be greatly reduced.

The particles are held together in the present invention for some time by the gel carrier even in a liquid environment. At the bone site, the gel will provide a means to fix the particles for a period of time.

In addition, since the microparticles are relatively small, the microparticles are more widely distributed in the desired site through injection. The viscosity of the gel carrier can be prepared as desired in a "dilute and flowing" consistency medium or "dense and robust" consistency. This can be done, for example, by adjusting the content of other components of the composition comprising glycerin and sodium carboxymethylcellulose.

The particle size of the ceramic particulate in the tissue enhancing material can be reduced in this application. That is, the material that can be used will be 37 to 63 μm CaHA particulates. The major advantage of larger particle sizes in soft tissues is the lack of migration by cellular mechanisms that can transport particulates to distant organ sites. However, the probability of this occurrence will be greatly reduced, for example in the case of particulates contained in the strut bone cavity. In addition, CaHA, known to bind to bone, further reduces the degree of migration.

In addition, the inventors have discovered that the tissue enhancing substance according to the present invention may be the main component of a toxic substance useful in the field of transplantation. Specifically, it has been found that the tissue enhancing substance according to the present invention exhibits some surprising properties when exposed to air and dried. When extruded directly from a syringe or through a needle or catheter, a surprisingly tacky and flexible "string" of particles will occur after exposure to air. It is clear that the material is substantially dehydrated and it is possible to form various shapes of material into sheets if desired. The material may be shaped and shaped like clay or sculpted with a suitable device to produce a preliminary shape for implantation. Advantages of these materials are tackiness, formability and high concentration of particulates per unit volume.

The following examples show characteristic embodiments of the invention. All parts and percentages are by weight unless otherwise indicated.

<Example 1>

Preparation of Gel

A mixture of 15% glycerin, 85% water (based on the combined weight of water and glycerin) and 3.25% NaCMC (again based on the total amount of liquid components) was prepared in the following manner.

9.303 g of glycerin and 2.016 g of NaCMC were combined in a vessel. The mixture was then slowly added to 52.718 g of water for stirring in a vessel large enough for the batch size and mixed for 30 minutes at medium speed using an electric mixer. The gel was left for a minimum of 4 hours.

<Example 2>

Preparation of Enhancing Compositions

An aqueous glycerin / NaCMC gel (44.04 g, prepared in Example 1) was placed in a mixing vessel large enough for the batch size. Thoroughly smooth, round, substantially spherical CaHA particles (55.99 g) having a uniform particle size of 75 to 125 μm thoroughly using an electric mixer for 5 minutes at low speed until all particles are homogeneously distributed in a uniform suspension in the gel. Blending is done. The blended material was packaged into a 3 cc polysulfone cartridge and sterilized for 60 minutes in an autoclave at 121 ° C.

<Example 3>

Properties of Enhancing Compositions

The gel prepared in Example 1 and the augmentation medium prepared in Example 2 were examined by a parallel plate rheometer (Haeake RS 100). The tests included the measurement of rheological properties as a function of applied stress (stress ramp), constant stress and then strain (reduction of creep / recovery) upon recovery of zero stress and complex modulus using vibration stress (frequency sweep) within the viscoelastic limit of the composition. The measurement of was included. The results demonstrated that the behavior of the gel and enhancement composition was the same both before and after sterilization. For example, this was demonstrated in FIG. 3 showing the viscosity of the gel and enhancement material before and after sterilization as a function of applied stress of 10 to 1000 Pa. The shapes of the curves were similar and demonstrated the shear weakening properties of this material. Other measurements are shown in the table below. Viscosity was measured at 500 Pa in stress ramp measurements. Elastic modulus was measured under a vibration force of 100 Pa at 1 hertz. Tanδ, the ratio of inelastic modulus to elastic modulus, was measured under a vibrational force of 100 Pa at 1 hertz. The maximum deflection γ _{max '} was measured after a constant 100 Pa applied stress of 120 seconds. % Recovery was measured after 200 seconds of relaxation, followed by a constant 100 Pa applied stress of 120 seconds.

Rheological results of gels and enhancement materials obtained on a Haake RS100 controlled stress rheometer using 2 cm parallel plates Prepared Gel Prepared Enhancer Composition Sterilized Augmentation Composition Viscosity at 500 Pa Stress (Cp) 603,000 4,610,000 4,340,000 Elastic modulus (100 Pa at 1 Hz) 408 2520 2684 tanδ (100 Pa at 1 Hz) 0.461 0.453 0.429 γ _{max '} 2.227 0.367 0.345 % Recovery 44.99 45.50 46.96

<Example 4>

Preparation of Gel

A mixture of 25% glycerin, 75% water and 2.25% NaCMC (based on the combined weight of water and glycerin) was prepared in the following manner.

87.90 g of glycerin and 7.91 g of NaCMC were combined in a container large enough to mix the total mass. The mixture was then slowly added to 263.71 g of water for stirring in a vessel large enough for the batch size and mixed for 30 minutes at medium speed using an electric mixer. The gel was left for a minimum of 4 hours.

Example 5

Preparation of Enhancing Compositions

Aqueous glycerin / NaCMC gel (38.52 g, prepared in Example 1) was placed in a mixing vessel large enough for the batch size. Thoroughly smooth, round, substantially spherical CaHA particles (74.86 g) having a uniform particle size of 37 to 63 μm using an electric mixer for 5 minutes at low speed until all particles are homogeneously distributed in a uniform suspension in the gel. Blending is done.

<Example 6>

In most cases, augmentation compositions comprising polysaccharide gel / particulate calcium hydroxyapatite suspensions are relatively inexpensive to inject or extrude into the air because of the relatively lack of resistance. However, greater force was required to inject the enhancement composition into the tissue and this force was significantly affected by the shape of the particulate matter. This was followed by various volume percent calcium hydroxyapatite particles with different shapes according to the procedure of Example 2, 75% water, 25% glycerin and 2.25% sodium carboxymethylcellulose (based on the combined weight of water and glycerin) Illustrated by making a sterile suspension of the polysaccharide gel made up. The prepared suspension was placed in a standard 3 cm ³ syringe. The force applied to the plunger was then measured to extrude the polysaccharide gel / particle suspension through an 18 gauge needle at a rate of 1 inch / minute. In addition, the force was measured for the needle inserted into the turkey follicle tissue as a clinically used analog. Spray dried particles of calcium hydroxyapatite had a flat and uniform appearance under microscope at 40 times magnification, regardless of their shape. The particles were evenly distributed within the particle size range. The results are shown in Table 2 below.

Calcium hydroxyapatite particles in gel Power, lbs Size, μm Particle shape Volume,% solids air group 38 to 63 Spherical / flat 35 4.5 6.0 38 to 63 Spherical / flat 40 5.9 7.2 38 to 63 irregular 40 8.0 ^* 9.6 ^* 74 to 100 Irregular / flat 37 5.5 > 30 74 to 100 Irregular / flat 41 > 30 > 30 74 to 100 Spherical / flat 42 4.8 5.5 ^{* This} is a result of the average mismatch due to the complete failure of the needle sporadically occurring during the test, requiring replacement of the needle.

This data correlated with animal experiments where it was impossible to inject irregular particles into tissue even when the% solids were reduced to less than 25% by volume or 16 gauge needles were used.

<Example 7>

A sterile sample of polysaccharide gel / particulate calcium hydroxyapatite suspension was prepared using a series of specified particle size ranges. The distribution of particles was uniform within each particle size range. The particles were flat and round calcium hydroxyapatite, and the gel had the same configuration as in Example 1. Calcium hydroxyapatite particles accounted for 36% by volume of the suspension. The extrusion force into the air for each suspension having each designated particle size range was measured using a standard 3 cm ³ syringe in the same manner as in Example 6. The results are shown in Table 3 below, and proved that the difference in extrusion force hardly occurs as the particle size increases as long as the particle size is maintained in a uniform and narrow distribution range.

Size distribution, μm Extrusion force, lbs 40 to 60 2.3 62 to 74 2.0 40 to 74 2.6 82 to 100 2.3 100 to 125 2.2 125 to 149 2.4 100 to 149 2.4

<Example 8>

Various weight percent sodium carboxymethylcellulose, water and glycerin were prepared in four different gels according to the procedure of Example 1 except using different ratios. Each gel was then blended with about 40 volume percent calcium hydroxyapatite particles having a distribution of 38-63 μm. The gel / particle blend was then placed in a standard 3 cm ³ syringe equipped with 18 gauge, 20 gauge and 22 gauge needles. The extrusion force into the air of the blend was measured in the same manner as in Example 3. The results are shown in Table 4 below.

weight% Power, lbs % NaCMC ^* glycerin water 18 gauge 20 gauge 22 gauge 1.0 60 40 3.6 6.4 7.7 1.5 50 50 4.0 5.8 8.2 2.0 30 70 4.1 6.3 7.7 2.0 40 60 4.8 7.0 9.2 ^* Sodium carboxymethylcellulose. The weight percent of sodium carboxymethylcellulose is based on the total weight of glycerin and water.

Example 9

Preparation of Augmented Compositions Using Polystyrene Microbeads

A gel consisting of 4.93% glycerin, 93.60% water and 1.48% NaCMC was prepared by the method described in Example 1. Spherical polystyrene beads (12.79 g) having a particle size range of 100 to 500 μm were thoroughly blended for 5 minutes at low speed using an electro-electric mixer until all particles were homogeneously distributed in a homogeneous suspension in 28.43 g of gel. The density of the polystyrene beads was 1.07 g / cc as measured by a helium hydrometer. The blended material was packaged into a 10 cc polypropylene syringe cartridge and sterilized for 60 minutes in an autoclave at 121 ° C. Polystyrene beads remained homogeneously distributed in the gel carrier. Rheological properties were measured as described in Example 3. Viscosity was measured at 100 Pa in the stress ramp measurement. Elastic modulus was measured under a vibrational force of 20 Pa at 1 hertz. The tanδ, the ratio of inelastic modulus to elastic modulus, was measured under a vibrational force of 20 Pa at 1 hertz. The maximum deflection γ _{max '} was measured after a constant 10 Pa applied stress of 120 seconds. % Recovery was measured after 200 seconds of relaxation, followed by a constant 10 Pa applied stress of 120 seconds. The results are shown in Table 5 below.

Rheological results of gel and polystyrene-enhancing materials obtained using a Haake RS100 controlled stress rheometer using 2 cm parallel plates Prepared Gel Prepared Enhancer Composition Sterilized Augmentation Composition Viscosity at 100 Pa Stress (Cp) 2,050 47,900 9,630 Elastic modulus (20 Pa at 1 Hz) 11 31 16 tanδ (20 Pa at 1 Hz) 1.348 1.320 2.067 γ _{max '} (at 10 Pa) 27.406 5.717 47.873 % Recovery rate 22.4 23.4 1.6

<Example 10>

Preparation of Augmentation Compositions Using Polymethylmethacrylate Microbeads

A gel consisting of 9.80% glycerin, 88.24% water and 1.96% NaCMC was prepared by the method described in Example 1. Spherical polymethylmethacrylate beads (12.78 g) having a uniform particle size of 100 to 180 μm were used on an electric planetary mixer for 5 minutes at low speed until all particles were homogeneously distributed in a uniform suspension in 28.84 g of gel. Blended thoroughly. The density of the polymethylmethacrylate beads was 1.21 g / cc as measured by a helium hydrometer. The blended material was packaged into a 10 cc polypropylene syringe cartridge and sterilized for 60 minutes in an autoclave at 121 ° C. Polymethylmethacrylate beads remained homogeneously distributed in the gel carrier. Rheological properties were measured as described in Example 6. Viscosity was measured at 100 Pa in the stress ramp measurement. Elastic modulus was measured under a vibrational force of 20 Pa at 1 hertz. The tanδ, the ratio of inelastic modulus to elastic modulus, was measured under a vibrational force of 20 Pa at 1 hertz. The maximum deflection γ _{max '} was measured after a constant 20 Pa applied stress of 120 seconds. % Recovery was measured after 200 seconds of relaxation followed by a constant 20 Pa applied stress of 120 seconds. The results are shown in Table 6 below.

Rheological results of gel and polymethylmethacrylate enhancing materials obtained using a Haake RS100 controlled stress rheometer using 2 cm parallel plates Prepared Gel Prepared Enhancer Composition Sterilized Augmentation Composition Viscosity at 100 Pa Stress (Cp) 58,700 482,000 22,200 Elastic modulus (20 Pa at 1 Hz) 58 212 42 tanδ (20 Pa at 1 Hz) 0.785 0.705 1.934 γ _max 2.895 1.111 0.211 % Recovery rate 53.1 48.2 20.9

<Example 11>

Preparation of Enhancing Compositions

Use of Glass Microbeads

The method described in Example 1 produced a gel consisting of 14.56% glycerin, 82.52% water and 2.91% NaCMC. 30.42 g of spherical glass beads having a uniform particle size of 30 to 90 microns were thoroughly blended at low speed for 5 minutes using an electric planetary mixer so that all particles were homogeneously distributed in a uniform suspension in 29.27 g of gel. The density of gel beads was 2.54 g / cc as measured by helium specific gravity method. The blended material was packaged in a 10 cc polypropylene syringe cartridge and sterilized at 121 ° C. for 60 minutes in an autoclave. The glass beads remained homogeneously distributed in the gel carrier. Rheological properties were measured as described in Example 3. Viscosity was measured at 500 Pa by stress ramp measurement. Elastic modulus was measured under vibration force of 100 Pa at 1 hertz. The ratio of inelastic modulus to elastic modulus, tan δ, was measured under vibration force of 100 Pa at 1 hertz. The maximum deflection γ _{max '} was measured after 120 seconds of constant 100 Pa applied stress. The percent recovery was measured after 120 seconds of constant 100 Pa applied stress followed by 200 seconds. The results are shown in Table 7 below. Sterile enhancement material was filled into a 3 cc syringe cartridge and extruded with a 3.5 inch gauge spiral needle. The average extrusion force was 14.63 pounds from 0.09 pounds standard deviation.

Rheological results of gel and glass enhancement materials obtained using a Haeake RS100 controlled stress rheometer using 2 cm parallel plates Prepared Gel Augmentation composition in a prepared state Sterilized Augmentation Composition Viscosity at 500 Pa Stress (Cp) 135,000 803,000 569,000 Elastic Modulus (100 Pa at 1 Hz) 256 699 570 tan δ (100 Pa at 1 Hz) 0.545 0.557 0.692 γ _{max '} 4.302 1.195 3.259 % Recovery 36.3 37.7 24.7

<Example 12>

Preparation of Enhancing Compositions

Use of stainless steel microbeads

The method described in Example 1 produced a gel consisting of 4.76% glycerin, 90.48% water and 4.76% NaCMC. Mixing time was extended from 30 minutes to 1 hour for this composition. 95.19 g of spherical stainless steel beads having a uniform particle size of 60 to 120 microns were thoroughly blended at low speed for 5 minutes using an electric planetary mixer so that all particles were homogeneously distributed in a uniform suspension in 28.69 g of gel. The density of the stainless steel beads was 7.93 g / cc as measured by helium specific gravity method. The blended material was packaged in a 10 cc polypropylene syringe cartridge and sterilized at 121 ° C. for 60 minutes in an autoclave. Stainless steel beads remained homogeneously distributed in the gel carrier. Rheological properties were measured as described in Example 3. Viscosity was measured at 500 Pa by stress ramp measurement. Elastic modulus was measured under vibration force of 100 Pa at 1 hertz. The ratio of inelastic modulus to elastic modulus, tan δ, was measured under vibration force of 100 Pa at 1 hertz. The maximum deflection γ _{max '} was measured after 120 seconds of constant 100 Pa applied stress. The percent recovery was measured after 120 seconds of constant 100 Pa applied stress followed by 200 seconds. The results are shown in Table 8 below. Sterile enhancement material was filled into a 3 cc syringe cartridge and extruded with a 3.5 inch 20 gauge helical needle. The average extrusion force was 30.84 pounds from 0.37 pounds standard deviation.

Rheological results of gel and stainless steel enhancement materials obtained using a Haeake RS100 controlled stress rheometer using 2 cm parallel plates Prepared Gel Prepared Enhancer Composition Sterilized Augmentation Composition Viscosity at 500 Pa Stress (Cp) 8,150,000 42,400,000 23,600,000 Elastic Modulus (100 Pa at 1 Hz) 1663 8411 5085 tan δ (100 Pa at 1 Hz) 0.335 0.366 0.400 γ _{max '} 0.336 0.110 0.197 % Recovery 62.8 64.5 54.3

Example 13

Preparation of Enhancing Compositions

Use of xanthan gum gel former

The method described in Example 1 produced a gel consisting of 13.8 parts of glycerin, 78.2 parts of water and 8 parts of xanthan gum polysaccharide. The viscosity of the gel, measured using a Brookfield rheometer, was 51,250 cps. Calcium hydroxyapatite granules ranging in diameter from 75 to 125 microns were thoroughly blended at low speed for 5 minutes using an electric planetary mixer so that all particles were homogeneously distributed in a uniform suspension in the gel. The blended material was packaged in a polypropylene syringe cartridge and sterilized at 121 ° C. for 60 minutes in an autoclave. Particulate hydroxyapatite remained homogeneously distributed in the gel carrier. Centrifugation of the cartridge with the IEC Clinical Centrifuge (Model 0M428) for 5 minutes at a force of 1016 x g did not precipitate the particles in the gel carrier. (This result suggests that the particles will not settle over an extended period of time because the gel's elastic limit will not be exceeded.) The enhancement material was extruded from the syringe cartridge through a 1.5 inch long 18 gauge needle. The extrusion force required was 3.90 pounds.

<Example 14>

Preparation of Enhancing Compositions

Use of xanthan gum gel former and isopropyl alcohol

The method described in Example 1 produced a gel consisting of 64.4 parts of isopropyl alcohol, 27.6 parts of water and 8 parts of xanthan gum polysaccharide. The viscosity of the gel, measured using a Brookfield rheometer, was 37,500 cps. Calcium hydroxyapatite granules ranging in diameter from 75 to 125 microns were thoroughly blended at low speed for 5 minutes using an electric planetary mixer so that all particles were homogeneously distributed in a uniform suspension in the gel. The blended material was packaged in a polypropylene syringe cartridge and sterilized at 121 ° C. for 60 minutes in an autoclave. Particulate hydroxyapatite remained homogeneously distributed in the gel carrier. Centrifugation of the cartridge with the IEC Clinical Centrifuge (Model 0M428) for 5 minutes at a force of 1016 x g did not precipitate the particles in the gel carrier. (This result suggests that the particles will not settle over an extended period of time because the gel's elastic limit will not be exceeded.) The enhancement material was extruded from the syringe cartridge through a 1.5 inch long 18 gauge needle. The required extrusion force was 7.34 pounds.

<Example 15>

Gels were prepared according to Example 1 and enhancement media were prepared according to Example 2. The patient was then anesthetized appropriately and then drilled a hole (larger than 18 gauge needles) at the entry point into the neck, head and femoral region of the femur from the soft sponge of the larger femur. An 18 gauge needle 3.5 inches in length was connected to a syringe containing augmentation medium using a Luer engagement connection. The enhancement medium was then injected through the hole in the bone. Sufficient material was injected to act as a skeleton for bone formation and bone growth between the femoral consolidation particles and the femoral head of the femur to reduce the risk of fracture.

While the invention has been described in connection with its preferred embodiments, many other variations, modifications and other uses will be apparent to those skilled in the art without departing from the scope of the invention. Accordingly, the invention should not be limited by the specific disclosure herein, but only by the appended claims.

Claims (56)

A polysaccharide gel having a viscosity of 200,000 to about 350,000 centipoise, wherein the polysaccharide gel is homogeneously suspended in a tissue enhancing material prior to augmentation of the desired tissue site and during introduction of the tissue enhancing material into the desired site. A biomiscible resorbable lubricity carrier for suspending a biomaterial in a tissue enhancing material to retain the material. The carrier of claim 1 wherein the polysaccharide gel is an aqueous polysaccharide gel. The polysaccharide gel of claim 1 wherein the polysaccharide gel consists of an intramolecular complex of cellulose polysaccharides, starches, chitin, chitosan, hyaluronic acid, hydrophobically modified polysaccharides, alginates, carrageenan, agar, agarose, polysaccharides, oligosaccharides and macrocyclic polysaccharides. A carrier comprising a polysaccharide selected from the group. 4. The carrier of claim 3, wherein the polysaccharide gel comprises cellulose polysaccharides. The carrier according to claim 4, wherein the cellulose polysaccharide is selected from the group consisting of sodium carboxymethylcellulose, agar methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, microcrystalline cellulose and oxidized cellulose. 6. The carrier of claim 5, wherein the cellulose polysaccharide is sodium carboxymethylcellulose. The carrier of claim 1, wherein the polysaccharide gel comprises a solvent selected from the group consisting of water and aqueous alcohol. 8. The carrier of claim 7, wherein the aqueous alcohol is selected from the group consisting of aqueous glycerol, aqueous isopropyl alcohol, aqueous ethanol, aqueous ethylene glycol and mixtures thereof. The carrier of claim 2, further comprising glycine. 10. The carrier of claim 9, wherein water and glycerin are present in the aqueous polysaccharide gel in a ratio of about 20 to 90:80 to 10. The carrier of claim 10, wherein water and glycerin are present in the gel at a ratio of about 85:15. The carrier of claim 1, wherein the biomaterial is selected from the group consisting of ceramics, plastics, and metals. 13. The carrier of claim 12, wherein the biomaterial is a ceramic. The carrier of claim 13, wherein the ceramic comprises circular, substantially spherical, biomiscible, substantially non-resorbable finely divided ceramic particles. 15. The carrier of claim 14, wherein the ceramic particles are selected from the group consisting of calcium phosphate particles, calcium silicate particles, calcium carbonate particles and alumina particles. 16. The carrier of claim 15, wherein the ceramic particles are calcium phosphate particles. The method of claim 16, wherein the calcium phosphate particles are calcium hydroxyapatite particles, tetracalcium phosphate particles, calcium pyrophosphate particles, tricalcium phosphate particles, octacalcium phosphate particles, calcium fluoroapatite particles, calcium carbonate apatite particles and mixtures thereof. A carrier selected from the group consisting of. 18. The carrier of claim 17, wherein the calcium phosphate particles are calcium hydroxyapatite particles. The carrier of claim 1 wherein the desired tissue site is a bone site. 20. The carrier of claim 19, wherein the desired tissue site is a bone site of osteoporosis. A biomaterial to augment the desired tissue site and a biomiscible resorbable lubricity carrier for the biomaterial, the carrier comprising a polysaccharide gel having a viscosity of 200,000 to about 350,000 centipoise, the carrier being a desired tissue A biomiscible composition for augmenting tissue, wherein the biomaterial is homogeneously suspended in the biomiscible composition prior to augmentation of the site and during introduction of the biocompatible composition into the desired site. The composition of claim 21, wherein the polysaccharide gel is an aqueous polysaccharide gel. 22. The polysaccharide gel of claim 21 wherein the polysaccharide gel consists of an intramolecular complex of cellulose polysaccharide, starch, chitin, chitosan, hyaluronic acid, hydrophobically modified polysaccharide, alginate, carrageenan, agar, agarose, polysaccharide, oligosaccharide and macrocyclic polysaccharide. A composition comprising a polysaccharide selected from the group. The composition of claim 23, wherein the polysaccharide gel comprises cellulose polysaccharides. The composition of claim 24 wherein the cellulose polysaccharide is selected from the group consisting of sodium carboxymethylcellulose, agar methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, microcrystalline cellulose and oxidized cellulose. The composition of claim 25, wherein the cellulose polysaccharide is sodium carboxymethylcellulose. The composition of claim 21, wherein the polysaccharide gel comprises a solvent selected from the group consisting of water and aqueous alcohol. 28. The composition of claim 27, wherein the aqueous alcohol is selected from the group consisting of aqueous glycerol, aqueous isopropyl alcohol, aqueous ethanol, aqueous ethylene glycol and mixtures thereof. The composition of claim 22 further comprising glycine. 30. The composition of claim 29, wherein water and glycerin are present in the aqueous polysaccharide gel in a ratio of about 20 to 90:80 to 10. 31. The composition of claim 30, wherein water and glycerin are present in the aqueous polysaccharide gel in a ratio of about 85:15. The composition of claim 21, wherein the biomaterial is selected from the group consisting of ceramics, plastics, and metals. 33. The composition of claim 32, wherein the biomaterial is a ceramic. 34. The composition of claim 33, wherein the ceramic comprises circular, substantially spherical, biomiscible, substantially non-resorbable finely divided ceramic particles. 35. The composition of claim 34, wherein the ceramic particles are selected from the group consisting of calcium phosphate particles, calcium silicate particles, calcium carbonate particles and alumina particles. 36. The composition of claim 35, wherein the ceramic particles are calcium phosphate particles. The method of claim 36, wherein the calcium phosphate particles are calcium hydroxyapatite particles, tetracalcium phosphate particles, calcium pyrophosphate particles, tricalcium phosphate particles, octacalcium phosphate particles, calcium fluoroapatite particles, calcium carbonate apatite particles and mixtures thereof. The composition is selected from the group consisting of. 38. The composition of claim 37, wherein the calcium phosphate particles are calcium hydroxyapatite particles. The composition of claim 21, wherein the desired tissue site is a bone site. 40. The composition of claim 39, wherein the desired tissue site is a bone site of osteoporosis. In a biomiscible composition for augmenting tissue, a polysaccharide gel carrier comprising a biomaterial for augmenting a desired tissue site and a biomiscible, resorbable, lubricious carrier for the biomaterial, and having a viscosity of 200,000 to about 350,000 centipoise Wherein the carrier comprises a biomiscible composition for augmenting tissue prior to the augmentation of the desired tissue site and maintaining the biomaterial homogeneously suspended in the biocompatible composition during the introduction of the biocompatible composition to the desired site. . Substantially a suspension medium comprises a dehydrated biomiscible resorbable suspension medium for a biomaterial to augment a desired tissue site and a dehydrated polysaccharide gel for retaining the biomaterial suspended in the implant composition. Dehydrated biomiscible composition. 43. The composition of claim 42, wherein the composition is molded into a preform for implantation into a desired tissue site. The polysaccharide gel of claim 42 wherein the polysaccharide gel consists of an intramolecular complex of cellulose polysaccharide, starch, chitin, chitosan, hyaluronic acid, hydrophobically modified polysaccharide, alginate, carrageenan, agar, agarose, polysaccharide, oligosaccharide, and macrocyclic polysaccharide. A composition comprising a polysaccharide selected from the group. 45. The composition of claim 44, wherein the polysaccharide gel comprises cellulose polysaccharides. 46. The composition of claim 45, wherein the cellulose polysaccharide is selected from the group consisting of sodium carboxymethylcellulose, agar methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, microcrystalline cellulose and oxidized cellulose. 47. The composition of claim 46, wherein the cellulose polysaccharide is sodium carboxymethylcellulose. 43. The composition of claim 42, wherein the biomaterial is selected from the group consisting of ceramics, plastics and metals. 49. The composition of claim 48, wherein the biomaterial is a ceramic. 50. The composition of claim 49, wherein the ceramic comprises circular, substantially spherical, biomiscible, substantially non-resorbable finely divided ceramic particles. 51. The composition of claim 50, wherein the ceramic particles are selected from the group consisting of calcium phosphate particles, calcium silicate particles, calcium carbonate particles and alumina particles. 52. The composition of claim 51, wherein the ceramic particles are calcium phosphate particles. 53. The method of claim 52 wherein the calcium phosphate particles are calcium hydroxyapatite particles, tetracalcium phosphate particles, calcium pyrophosphate particles, tricalcium phosphate particles, octacalcium phosphate particles, calcium fluoroapatite particles, calcium carbonate apatite particles and mixtures thereof. The composition is selected from the group consisting of. 54. The composition of claim 53, wherein the calcium phosphate particles are calcium hydroxyapatite particles. Drying the biomiscible composition comprising a biomaterial to augment a desired tissue site and a biomiscible resorbable lubricity carrier for the biomaterial, the carrier comprising a polysaccharide gel having a viscosity of about 20,000 to about 350,000 A method of making a substantially dehydrated biomiscible composition for implantation into a desired tissue site, comprising. 56. The method of claim 55, further comprising molding the substantially dehydrated biomiscible composition into a preform for implantation into a desired tissue site.