JP2003507351A - Tissue enhancers and methods - Google Patents

Abstract

(57) [Summary] Permanent biocompatible material for soft tissue augmentation. The biocompatible material comprises a matrix of smooth, rounded, finely divided, substantially spherical, particles of a biocompatible ceramic material that are in close proximity or in contact with each other, the particles being enhanced. A scaffold or lattice is provided for the growth of intact soft tissue that is self-directed three-dimensionally oriented at the site. The enhancing material can be uniformly suspended in a biocompatible, resorbable, lubricating gel carrier comprising the polysaccharide. This helps improve delivery of the augmentation material by injecting into the tissue site where augmentation is desired. The augmenting material is particularly suitable for augmenting the internal urethral sphincter, treating incontinence, filling soft tissue gaps, creating soft tissue blebs, treating vocal cord paralysis, and breast transplantation. The enhancing material may be injected intradermally, or subcutaneously, or may be implanted.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a soft tissue augmentation, more particularly to a urethral sphincter augmentation for the treatment of incontinence, for filling a soft tissue void or for producing a soft tissue bleb, for a breast transplant. And a biocompatible composition for the treatment of unilateral vocal cord paralysis. The invention also relates to gel carriers for biocompatible compositions.

[0002]

[Prior art]

Examples of biocompatible materials that have been proposed for use in soft tissue augmentation in plastic surgery practice include collagen, gelatin beads, natural or synthetic polymers such as polytetrafluoroethylene and silicone rubber, and poly. It includes various hydrogel polymers such as acrylonitrile-polyacrylamide hydrogel.

Most often, biomaterials are augmented by means of injectable compositions that include biomaterials that function as lubricating oils or biocompatible fluids to improve the injectability of biomaterial suspensions. Derived from the desired organizational site. This injectable biomaterial composition is applied intradermally or subcutaneously to humans or other mammals to enhance soft tissue, correct congenital, acquired, or cosmetic abnormalities. It can be introduced at the tissue site by injection with a syringe. They may also be injected into internal tissues such as those that define the sphincter, augmenting such tissues for the treatment of incontinence and unilateral vocal cord paralysis.

Ersek et al., UK Patent Application No. 2,227,176, discloses a micro for filling surgically recessed scars, asymmetric orbital bases, and superficial bone abnormalities with particles of about 20-3000 microns. With regard to the method of implantation, the microparticles can be injected with a suitable physiologic medium and hypodermic needles and syringes, such as under the scarred bottom, under the skin area of the depression, and under the periosteum or periosteum due to surface irregularities of bone and cartilage It is injected in place.
Textured particulates can be used, including silicon, polytetrafluoroethylene, ceramics, or other inert materials. In such instances, there is a requirement for hard materials, biocompatible materials such as calcium salts with hydroxyapatite or crystalline, biocompatible ceramics, biocompatible materials such as stainless steel particles or glass. Certain metals can be used.
Suitable physiological media have been suggested to include saline, various starches, polysaccharides, and organic oils or fluids.

Wallace et al., US Pat. No. 4,803,075, discloses an aqueous suspension of a particulate biocompatible natural or synthetic polymer to improve the injectability of the biomaterial suspension. An injectable implant composition for soft tissue augmentation comprising a lubricating oil.

Berg et al., US Pat. No. 4,837,285, relates to a collagen-based composition for enhancing soft tissue repair, wherein the collagen is an absorbable matrix having an average pore size of about 50-350 microns. It is formed into beads and contains up to about 10% by volume of collagen based on the beads.

US Pat. No. 4,280,954 to Yannas et al. Relates to a collagen-based composition for surgical use, which composition is formed by contacting collagen with mucopolysaccharides. , These form the reaction product, after which
The reaction product is covalently crosslinked.

Lim US Pat. No. 4,352,883 discloses a method of encapsulating a core material in the form of living tissue or individual cells by forming a capsule of a polysaccharide gum. Thus, this polysaccharide gum can be gelled to form a mass-maintaining shape by exposure to changes such as pH changes or by exposure to polyvalent cations such as calcium.

Namiki's “Application of Teflon Paste
for Urinal Incontinence-Report of
Two Cases "Urol. Int. , Vol. 39, pp. 280-28
2, (1984) discloses the use of paste infusion of polytetrafluoroethylene in the subcutaneous area to treat urinary incontinence.

[0010] Drobeck et al., "Histologic Observation of
Soft Tissue Responses to Implanted,
Multifaceted Particles and Discs of
"Hydroxylapatite" Journal of Oral Maxi
Ilofacial Surgery, Vlo. 42, pp. 143-149,
(1984) disclose that ceramic hydroxylapatite implants implanted subcutaneously in rats and subcutaneously and subperiosteally in dogs have long-term and short-term effects on soft tissue. There is. The present invention uses hydroxylapatite in various sizes and shapes to determine if migration and / or inflammation occur.
It consists of transplanting in a time range of 7 days to 6 years.

[0011] Missiek et al., "Soft Tissue Responses to H"
ydroxylapatite Particles of Different
t Shapes "Journal of Oral Maxillofaci
al Surgery, Vol. 42, pp. 150-160, (1984) show that implanting hydroxylapatite in the form of sharp or round particles into cheek soft tissue pouches caused an inflammatory reaction at the implant site in the form of both particles. Disclosure. The weight of the particles was 0.5 grams each. However, the inflammation subsided sooner where the round hydroxylapatite particles were implanted.

Shimizu's “Subcutaneous Tissue Response”
ses in Rats to Injection of Fine Par
tickets of Synthetic Hydroxyapatite C
"eramic" Biomedical Research, Vol. 9, No.
2, pp. 95-111 (1988) describes subcutaneous implantation of microparticles of hydroxyapatite interspersed within tissue in the diameter range of about 0.65 to a few microns.
It discloses that it was phagocytosed by macrophages at a fairly early stage. On the other hand, larger particles with diameters of a few microns were not phagocytosed but were surrounded by numerous macrophages and multinucleated giant cells. It was also observed that the reaction of small tissues to hydroxyapatite particles was essentially a non-specific foreign body reaction without damaging the cells or tissues.

R. A. Appell's "The Artificial Urinary"
Sphincter and Peripheral Injection
s "Obstetrics and Gynecology Report R
ettort Vol. 2, No. 3, pp. 334-342, (1990)
This is a research article disclosing various means for treating urethral sphincter deficiency, and injectables such as irregularly shaped polytetrafluoroethylene micropolymer particles of about 4 to 100 microns in size, together with glycerin and polysorbate. Includes using.

[0014] Politano et al., "Perirethral Teflon Inje."
action for Urinal Incontinence "The J
annual of Urology, Vol. 111, pp. 180-183 (
1974) used polytetrafluoroethylene paste infused into the urethra and periurethral tissues to add bulk to these tissues, providing urinary control for both female and male patients with urinary incontinence. It discloses to recover.

“Migration and Gramuromato” by Malizia et al.
us Reaction After Peripheral Injec
“Tion of Polytef (Teflon)” Journal of t
he American Medical Association, Vol.
251, No. 24, pp. 3277-3281, June 22-29 (198
4) shows that although patients with urinary incontinence have been successfully treated by periurethral transplantation of polytetrafluoroethylene paste, studies on self-controlled animals have demonstrated migration of polytetrafluoroethylene particles from the test site. ing.

[0016] Claes et al., "Pulmonary Migration Followi.
ng Peripheral Polytetrafluoroethyl
ene Injection for Urinary Incontinen
ce ”The Journal of Urology, Vol. 142, pp
． 821-22, (September 1989) confirm the discovery of Malizia by reporting a clinically significant case of polytetrafluoroethylene paste particles translocating to the lung after periurethral implantation. .

Ersek et al., “Bioplastique: A New Textured”
Copolymer Micropatient Promises Per
manence in Soft-Tissue Augmentation "
Plastic and Reconstructive Surgery, V
ol. 87, No. 4, pp. 693-702, (April 1991) discloses the use of biphasic copolymers formed from fully polymerized and vulcanized methylmethylpolysiloxane mixed with Plasdone hydrogel to cleft the lip,
It is used for crushed scars of water acne, indentations resulting from liposuction, restoration of wrinkles between the eyebrows, and increased soft tissue of thin lips. The biphasic copolymer particles have not been found to be moved or absorbed by the body, are textured and have particle sizes different from 100-600 microns.

Lemperle et al., “PMMA Microspheres for In
tradeImplantation: PartI. Animal
Research ”Annals of Plastic Surgery,
Vol. 26, No. 1, pp. 57-63, (1991) has a diameter of 10 to 63.
Disclosed is the use of micron polymethylmethacrylate microspheres having a particle size of 50, which is used to compensate for a small deficiency in the dermis to treat wrinkles and acne scars.

Kresa et al., “Hydron Gel Implants in Voca
l Cords ”Otolarynology Head and Neck
Surgery, Vol. 98, No. 3, pp. 242-245, (Mar
ch1988) discloses a method of treating vocal cord conditioning with inadequate glottic closure, which involves applying to the vocal cord a shaped implant of hydrophilic gel previously dried to a glassy and stiff condition. It includes the introduction.

Hirano et al., “Transcutaneous Intrafold I
njection for Universal Vocal Cord P
analysis: Functional Results "Ann. Otoll
． Rhinol. Laryngol. , Vol 99, pp. 598-604 (1
990) discloses a technique of percutaneous silicone vocal cord injection in the treatment of glottal insufficiency due to unilateral vocal fold paralysis. This silicone injection is performed on a supine patient under local anesthesia and the needle is inserted through the cricothyroid space.

Hill et al., "Autologous Fat Injection for
Vocal Cord Mediation in the Can
in Larynx "Laryngoscope, Vol. 101, pp. Three
44-348 (April 1991) is the medialization of the vocal cords.
as an implantable material in place of Teflon collagen,
Disclosed is the use of self-fat, which is also viewed as a substitute for non-self injectable materials in vocal cord augmentation.

Mikaelian et al., “Lipoinjection for Unila”
“Teral Vocal Cord Paralysis” Laryngosc
ope, Vol. 101, pp. 4654-68 (May 1991), a commonly used procedure of Teflon paste infusion to improve voice volume in unilateral vocal cord paralysis is a number of procedures including over-infusion of Teflon to respiratory obstruction and unsatisfactory voice quality. It discloses that he has a disability. In this procedure, lipoinjection of fat, typically obtained from the abdominal wall, will impart a soft bulkyness to the injected vocal cords, thereby preserving its oscillatory performance. This infused fat is a self-material that can be recovered if over-infused in excess of need.

Strasnick et al., “Transcutaneous Teflon I
njection for Universal Vocal Cord P
analysis: An Update "Laryngoscope, Vol.
101, pp. 785-787 (Jully 1991) discloses a procedure for Teflon infusion to ensure laryngeal performance in the case of vocal cord disorders due to paralysis.

[0024]

[Means for Solving the Problems]

According to the present invention, it is possible to provide a permanent biocompatible substance for enhancing soft tissue and a method for using the same. Further, according to the present invention, it is possible to provide a gel carrier which is particularly advantageous for administering a biocompatible substance to a desired tissue enhancing site.

The biocompatible material comprises a fine-grained matrix of a smooth, round, substantially spherical biocompatible ceramic material that is in close proximity to or in contact with each other at the augmentation site, self, It provides a skeleton or lattice for growing soft tissue free of scars in three dimensions, with any orientation. The augmentation material is, for example, a homogeneous suspension, biocompatible, absorbable, lubricious, gel carrier, such as a polysaccharide. This may improve delivery of the enhancing material by injecting into the cell site where it is desired to enhance. The augmentation material is particularly suitable for urethral sphincter augmentation, treatment of incontinence, filling of soft tissue gaps, generation of soft tissue blebs, treatment of unilateral vocal cord paralysis, and breast transplantation. It can be injected intradermally or subcutaneously and can be implanted.

[0026]

DETAILED DESCRIPTION OF THE INVENTION

In cases of stress incontinence in women and incontinence such as after prostatectomy in men, it is necessary to compress the urethra to avoid leaking urine from the bladder and help tighten the sphincter.

The soft tissue augmentation material of the present invention includes an injection system that can add bulk and concentrate compression on the sphincter / urethra, thereby increasing lumen size via one or more injections of the augmentation material. And substantially reduce or eliminate stress urinary incontinence due to sphincter insufficiency in women and men.

The augmentation material is also used to fill and smooth soft tissue imperfections such as pockmarks and scars. In addition, the augmenting material can also be used for internal injection of the sound producing part of the larynx by changing the shape of this soft tissue mass. The procedure involves delivering the augmentation material to the treatment site, preferably by injection. The augmentation material or gel can also be used for breast transplants.

The augmentation material of the present invention comprises particles of a smooth, round, substantially spherical ceramic material. The term "substantially spherical" means that some particles of the invention are spherical,
Most particles of the invention exhibit the fact that their shape is spherical, ie spheroidal. FIG. 1 illustrates these spheroidal or substantially spherical features. The term "round" or "smooth and round" as used herein indicates the fact, even if the particles of the invention are not perfectly spherical, that they have angled ends. Absent. The particles must be of sufficient size to avoid phagocytosis, as discussed below. As the upper limit of particles,
It can be of a size suitable for the desired soft tissue cell enhancement. However, due to the introduction by injection, the upper limit of particle size is dictated by the particle injection device used.
That is, when injecting, it must be small enough to avoid clogging and aggregation of the syringe. A typical range for injection is from about 35 to 150 microns, preferably a narrow particle size range extending from about 35 microns or less,
More preferably, it extends from about 10-30 microns or less, and most preferably it is substantially the same as the particle size. For example, the ceramic material can have a non-uniform particle size distribution of about 35-65 microns, 75-100 microns, 100-125 microns. These are illustrative and not limiting. Three
Other narrow particle sizes can be used, within the overall size range of 5-150 microns. When discussing these ranges, it should be understood that, as a practical matter, particles outside the desired range will be present in the samples of the enhancement material of the present invention in small amounts. However, most of the particles in a given sample should be in the desired range. Preferably 90% of the particles, most preferably 95-
99% is in the desirable range.

The finely ground ceramic augmentation material is substantially non-resorbable and therefore does not require repeated corrections. Substantially non-resorbable means that some lysis of the enhancing material may occur in the long term but is slow enough to allow replacement with growing tissue cells. Since there are no amino acids in collagen and fibrinogen, there is no antigenic reaction. The ceramic material is highly biocompatible and can be injected through an 18 gauge or smaller inner diameter syringe.

The preferred ceramic material is calcium hydroxyapatite, also known as basic calcium orthophosphate or calcium hydroxyapatite, which is the natural mineral phase of teeth and bones. As an implant material, granular calcium hydroxyapatite is a sintered polycrystalline composite of calcium phosphate and has proven to be highly compatible in tissues.

One method of preparing dense, round or substantially spherical ceramic particles such as calcium hydroxyapatite is to prepare calcium hydroxyapatite having a particle size of about 20-40 wt% submicron. Adjust by spray drying the slurry. This material is commercially available and can be prepared by conventional methods in the art such as low temperature crystallization, hydrothermal crystallization methods, and solid-to-solid reactions. The slurry may also contain processing additives such as wetting agents and binders on the order of about 1-5% by weight. Preferred wetting agents include polysorbates, sodium nitrate, ammonium polyelectrolytes. Preferred binders include polyvinyl alcohol, dextrin, or carbowax.

By spraying the slurry through a nozzle, it is spray-dried to form droplets.
The droplets remove moisture by passing through a column of heated air. The substantially spherical, agglomerated particles collect at one end of the heated column.

The substantially spherical particles sinter in the crucible at about 1050 ° C. to 1200 ° C. for at least about 1 hour. Furthermore, for the lowest aggregation, approximately 800 ° C
An operation of pre-sintering at ~ 1000 ° C for about 1 hour may be employed.

After pre-sintering, the spherical particles are agitated and rotated to prevent the individual particles from seizing or agglomerating. A rotary machine calciner can be used for this purpose. During the agglomeration process by minimizing agglomeration of particles together, a furnace of this type rotates so that the inverted agglomerated particles on one particle are the other. Commercial sources of such dry atomized particles are CeraMed Corp. of Lakewood, Colorado. Is.

An alternative method of forming dense, spherical particles is rota-agglomeration (rota) formation.
ry agglomeration). Here, dense, submicrometer ceramic particles, such as calcium hydroxyapatite, are placed on a rotating bowl having a large diameter and a diameter of at least 3 feet (0.9 m).

The bowl is rotated about its axis at an angle of about 30 degrees. At this time, the rotation speed and angle are adjusted so that submicrometer particles can rotate across the surface of the bowl. Spraying a fine powder of a binder solution as described above sprays onto the particles at a rate that slightly moistens the particles. The action of rolling across the face of the bowl and the addition of the binder solution allows the formation of small rotating agglomerates to grow to such a size that the operation will continue. This operation is likened to forming a large snowball by rolling a small snowball on a hill while rotating it. The size of the bowl, the speed of rotation, which determines the size and density of the aggregates formed,
The operating conditions, such as the angle of rotation and the spray amount used, are familiar to the person skilled in the art. The agglomerated spherical particles can be sintered by a method similar to dry spray agglomeration.

The obtained sintered spherical particles are divided and classified by the size and a sieving operation using a sieve having a spherical mesh size. A commercial source of such rotationally agglomerated particles is CAM Implants, Inc., Leyden, Netherland.

Furthermore, polishing or smoothing the surface is accomplished by milling operations such as milling balls. An extra mini-grinding media can be used, but mixed (
To minimize contamination, spherical particles can also be ground on it. This can be done in a standard bottle grinder or a tilted rotary grinder so that a sufficient amount of pure water is added to the particles so they can rotate relative to each other. This can be as long as a few days to smooth the surface on round agglomerates. If the initial agglomerates are not round, they can be smooth, but not on rolling. The irregularly shaped agglomerates have a smooth surface. However, even though it has a smooth surface, the irregularly shaped aggregates, when sprayed onto tissue, can clog or interfere with the syringe needle, significantly increasing injection force.

By using a tilted rotary mill, spherical particles that have become agglomerates that are free of smaller particles can be washed. This can be accomplished by placing the agglomerates in purified water with milled water and rolling for a sufficient period of time (eg 1 hour). This process is repeated after the spin cycle until the supernatant is relatively clear, usually about 3 or 4 operations.

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

The smooth surface of the individual round, spherical particles is important for reducing and minimizing surface porosity. Surface smoothness can be improved by completing operations known in the art, such as surface-only milling.
It is preferred to minimize surface irregularities on individual particles so that when viewed under a microscope at 40X magnification, the surface appears to resemble that of smooth round beads. This is clear from FIG. And it is a micrograph of calcium hydroxyapatite particles having a particle size distribution of 38 to 63 micrometers. A smooth, round, substantially spherical, non-porous surface is evident.

The ceramic particles are suitably smooth, hard, rounded particles, preferably with a density on the order of about 75% to about 100%, and further, a ceramic material. (Eg calcium hydroxyapatite)
From about 95% to about 100% of the theoretical density is preferred. The last operation is also
Porosity on the surface of the calcium hydroxyapatite particles can be minimized to less than about 30%, desirably less than about 10%. By minimizing the surface porosity, smooth surface particles can be obtained, which is preferred. And thereby, the jagged, irregular surfaces can be removed to maximize the properties of the smooth, round particles that come into contact with each other and easily flow.

The present invention has been described in terms of calcium hydroxyapatite and other useful suitable materials. However, the present invention is not limited to materials based on calcium phosphate, materials based on alumina, and the like. However, by way of example and not limitation, tetracalcium phosphate.
te), calcium pyrophosphate, tricalcium phosphate (tricalci)
um phosphate, octacalcium phosphate (octacalcium)
Phosphate), calcium / fluorapatite, calcium carbonate / apatite, and combinations thereof. Other equivalent calcium-based configurations can be used, such as calcium carbonate and the like.

As noted above, the present invention, in contrast to particles with a more textured porous surface or apertures, that is jagged, irregular, and has straight edges The individual ceramic particles used in have generally smooth, round, preferably spherical shapes. The smooth round shape allows it to be easily extruded by the ceramic particles to flow with reduced friction from the syringe to the tissue site where soft tissue augmentation is desired. Once at the tissue site, the ceramic particles can provide a matrix or scaffolding for autogenous tissue growth.

As noted above, particle sizes in the range of about 35 micrometers to about 150 micrometers are optimal for minimizing injection of phagocytotic particles and facilitating injection. Phagocytosis is the movement of smaller particles, on the order of 15 micrometers or less, that are taken up by cells and taken up by the lymphatic system, from the site where the augment was introduced into the tissue, typically by injection. Then, phagocytosis occurs.

At the lower end, particles larger than 15 micrometers, typically larger than 35 micrometers, are too large to be phagocytosed, and the known sizing
Can be easily separated by technique. Therefore, producing the most desirable narrow or equivalent particle size ranges for this invention is relatively simple.

Also due to the fact that such a smooth, round, substantially spherical distribution of particles reduces friction, it is desirable to use a narrow equivalent particle size range of ceramic particles as a desirable enhancement site. Facilitates the injection of molecules with a needle from a syringe into skin tissue. This is the opposite of using more porous, textured, irregularly shaped particles that tend to increase frictional forces and are much more difficult to deliver by injection.

As indicated above, the particle size distribution or size range of the particle size of the ceramic material within the overall range of 35-150 micrometers is narrower, preferably in the range of equivalent particle sizes. Is minimized. This maximizes which autologous tissue growth (stimulated by the presence of the enhancer) can occur, the intraparticle void volume or interstitial volume. There is a larger interstitial volume between particles that are equal in size compared to particles that have a variable size distribution. In the context of this invention, the interstitial volume is the void space existing between particles of the enhancer that are near or in contact with each other.

For example, in a three-dimensional crystalline lattice structure such as a face-centered cube, a body-centered cube, or a simple cube, the percentage of void space (known as the atom packing factor) is They are 26%, 33% and 48%, respectively. It is independent of the diameter of the atom, or in this case, the particle. The void volume is larger because the ceramic particles are never as tightly packed as the atoms in the crystalline-like lattice structure. And thereby maximizing the growth of the voluntary organization. Moreover, in order to increase the similarity of crystalline-like structures, the interstitial openings determine the maximum size that particles can fit into the void spaces that normally occur in the structure. The largest interstitial space is at about 0.4 times the size of the average ceramic molecule in the particle size distribution.

Thus, if the particle size distribution is from about 35 micrometers to about 65 micrometers, the average particle size will be 50 micrometers. The maximum interstitial space is 50 × 0.4 = 20 micrometers. 20 micrometers
Packing is minimal because size particles are not present in the distribution. Similarly, with a particle size distribution of 75 to 125 micrometers, the average particle size is 100 micrometers and the maximum interstitial space is 100 × 0.4 = 40 micrometers. Packing is also minimized because 40 micrometer particles are not present in the distribution. Therefore, if the ceramic particles are restricted to a narrow size range or equivalent size distribution, maximization of the void volume will occur so that autologous tissue can grow.

Other suitable particle size distribution ranges include 35 to 40 micrometers, 62 to 74 micrometers, 125 to 149 micrometers, and other correspondingly narrow ranges can also be used.

In contrast, where there is a wide size distribution, smaller particles tend to group or move into the space between larger particles, resulting in a higher density of densely packed particles. Tends to become. This results in less interstitial space available between particles for infiltration and growth of autologous tissues such as fibroblasts and chondroblasts.

Due to the packing effect that occurs between large and small particles, tissue growth where the enhancer has a broad particle size distribution becomes denser and stiffer. In contrast, the use of particles that are equivalent in size, or having a narrow uniformly distributed particle size range, increases void volume within the particles. This allows penetration of spaces or fissures between particles by maximizing the amount of autogenous, or three-dimensional, randomly oriented, non-scarred soft tissue in growth. The more available, more interstitial space allows subsequent autologous tissue growth to be stimulated by entry of the enhancer into the matrix or scaffold provided by the enhancer, resulting in native tissue in close proximity to the enhancer or immediate tissue. It will be almost similar.

The process of soft tissue augmentation is a biocompatible enhancer that includes the desired particle size of the desired ceramic material to the tissue at the augmentation sites required to create bubbles or blisters. Can be caused by injection or insertion. Subsequent autogenous tissue growth into the matrix provided by the enhancer will be most similar to the surrounding tissue in terms of texture and properties. This is in contrast to that which occurs using the highest known procedures in which foreign body reactions are known to occur, especially with Teflon® enhancers.

Foreign body reaction is the body's reaction to foreign substances. A typical foreign body tissue response is
Caused by the expression of polymorphonuclear leukocytes near the material followed by macrophages.
If the material is non-bioactive, such as silicone, only a thin collagen encapsulation tissue forms. If the material is a stimulant, inflammation occurs, and
This eventually becomes the granulation tissue morphology. For ceramic materials such as calcium hydroxyapatite, there is minimal encapsulation, excellent biocompatibility with tissue cell growth directly on the surface of the substantially unencapsulated particles.

At the site where soft tissue augmentation is desired is determined as any tissue in a specifically defined location in the body with growth stimulated by the presence of a matrix of biocompatible enhancer. From the enhancement in the urethral sphincter such native tissue resembles the tissue present in the urethral sphincter. In the glottis, where the voice mechanism of the larynx is located, the native tissues from the augmentation of the larynx are similar to the tissues of the existing glottis. Autologous tissue from breast augmentation resembles existing tissue such as the breast. Autologous tissue for intradermal injection resembles the dermis. In a similar manner, enhancers are used by providing a three dimensional lattice in the surgical incision or trauma to avoid linear, layered contraction wound formation.

As mentioned above, the calcium hydroxyapatite particles used as an enhancer are biocompatible and fairly non-resorbable. Thus, the soft tissue augmentation procedure is permanent. Moreover, the use of calcium hydroxyapatite does not require the rigorous precautions that are required when using other enhancers such as collagen, which are needed for freezing for storage, shipping and antigenicity testing.

The rounded, spherical, smooth calcium hydroxyapatite particles enhance biocompatibility against autologous tissue reactions into the particle matrix and are substantially free of calcification. Jagged or irregular particles can irritate the tissue and cause calcification. In addition, due to the relative stability of the pores in the particles, surface porosity on the order of about 30% by volume or greater can also cause calcification. Smooth, round, fairly non-porous particles maintain mobility in the tissue. Thus, the autogenous tissue that develops in the particle matrix, where mobility is maintained, does not solidify. In contrast, the porous section of the individual particles does not move relative to the particles, so tissue ingress into the pores does not move and calcification can occur.

The particulate ceramic material can be suspended in a biocompatible, resorbable lubricating oil. An example of a lubricating oil is a polysaccharide gel that improves the delivery of enhancer by injection into the tissue site where augmentation is required. Preferred polysaccharides will be readily apparent to those of ordinary skill in the art. For example, the polysaccharides that may be utilized in the present invention include any suitable polysaccharide within the following classes of polysaccharides. cellulose/
A system modified by starch, chitin chitosan, hyaluronic acid, and hydrophobia (hydr
Ophobe modified system), alginates, carrageenan, agar, agarose, intramolecular complexes, oligosaccharides, and macrocycles.

Examples of polysaccharides that fall into four basic categories include: 1. Cellulose derivative, starch, guar, chitin, agarose, dextron
ron) -containing nonionic polysaccharides; 2. 2. Cellulose derivatives Starch derivatives, carrageenan, alginic acid, carboxymethyl chitin / chitosan, anionic polysaccharides including hyaluronic acid and xanthan; 3. 3. Cationic polysaccharides including cellulose derivatives, starch derivatives, guar derivatives, chitosan and chitosan derivatives (including chitosan lactate); and Patients with hydrophobia are polysaccharides including cellulose derivatives and alpha-emulsan. For example, the preferred polysaccharide used in the present invention is agar methylcellulose.
ulose), hydroxypropyl methylcellulose (hydroprop)
yl methylcellulose), ethyl cellulose (ethylce)
illose), microcrystalline cellulose, oxidising cellulose, chitin, chitosan, alginic acid, sodium alginate and xanthan gum.

Cellulose polysaccharide gels are particularly advantageous because of their viscoelastic nature. Offset fluidization is one of these characteristics. That is, a force is applied to it and the cellulosic polysaccharide gel flows more quickly. This facilitates mixing when solid particles are added to the gel. Off-set fluidization allows for easier delivery of tacky materials. Another characteristic of a material is its elasticity, such that it tends to recover its original shape after deformation. This is very important because the elastic nature of the gel allows it to suspend the enhancer, which has achieved a rather indefinite shelf life indefinitely. Materials of relatively high density may be suspended by this gel. For example, calcium hydroxyapatite contains 75 to 1
3.1 Spherical shaped, granular, with diameters up to 25 micrometers
At a density of 0 g / cc, 14.53 parts glycerin, 82.32 parts water and 3.15
It can be suspended indefinitely in a gel made up of parts NaCMC.

The tissue-enhancing substance and the cellulose polysaccharide gel are mixed and the tissue-enhancing substance is suspended in the gel, which can be done using conventional mixing equipment without adversely affecting the gel carrier. Therefore, the elastic nature of the gels of the present invention has additional advantages.
That is, the gel carrier does not destroy or lose its elastic properties. These processes are enhanced by changes in the recovery of the elastic properties of the gel, such recovery occurring within seconds once the hydrated gel is formed. Such rapid shape recovery due to its elastic nature is also very important for placement and accumulation when implanted in living tissue. The recovery of the more viscous nature helps to accumulate on behalf of the substance once the force of injection has been removed, minimizing internal bleeding.

Any solvent suitable for the cellulose polysaccharide gel can be used in the present invention. For example, the gel may be an aqueous cellulose polysaccharide gel. Alternatively, the solvent may be an aqueous alcohol, including, for example, glycerol, isopropyl alcohol, ethanol, ethylene glycol and mixtures thereof. Suitable solvents for other gel carriers will be apparent to those skilled in the art. Surfactants, additives, p
H-buffers, and other additives, will also be apparent to those skilled in the art and can be used. Pharmaceutically active substances, such as growth factors, antibiotics, analgesics, etc., will also be apparent to those skilled in the art and can be used.

In addition, although the invention described herein relates to ceramic tissue enhancing materials, the cellulosic gel carriers of the invention can also be utilized as carriers for other tissue enhancing materials. For example, the cellulose polysaccharide gel carrier of the present invention can be utilized as a carrier for non-ceramic tissue enhancing substances such as glass, polymethylmethacrylate, silicon, titanium, and other metals. Other suitable non-ceramic tissue enhancing materials are those that are suspended and used as carriers for the present invention, as will be apparent to those of skill in the art.

The formulation of the gel depends on the number of elements: 1) molecular weight, rate of substitution,
And several other properties of the polysaccharide, 2) the solvent system used, 3) the final properties of the material needed for a particular application, etc. Generally, the ratio of cellulosic polysaccharide to solvent will vary between about 0.5-10: 98.5-90. For example, 8
In a 5:15 mixture of water and glycerin, the ratio is preferably 1.5-5.
: 98.5 to 95, and most preferably 2.5 to 3.5: 97.5, respectively.
~ 96.5.

Preferably, the gel comprises water, glycerin, sodium carboxymethyl cellulose. The gel is capable of keeping the particles of ceramic in suspension without settling for an indefinite period of time before use, especially for at least about 6 months. As other lubricants, those known in the field of the present invention can be used.

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

The viscosity of the gel is from about 20,000 to about 350,000 measured at 25 ° C. with a Brookfield viscometer at 16 revolutions per minute (16 rpm) with a RU # 7 axis.
It can vary between 0 centipoise, preferably about 150,000 to about 250,000 centipoise, and most preferably about 200,000 to about 250,000 centipoise. About 20,0
When the gel viscosity was less than 00 centipoise, no particles remained in the suspension. Also, at gel viscosities greater than about 350,000 centipoise, the gel became too viscous to mix.

In a preferred embodiment of the present invention, the polysaccharide is sodium carboxymethylcellulose and the sodium carboxymethylcellulose contained in the gel is
It has a high viscosity. In particular, sodium carboxymethylcellulose is a 1% aqueous solution of Hercules / Agualon Division Broc.
hure 250-10F EV. 7-29M "Sodium Carboxy
methylcellulose Physical and Chemical
l Properties, "pp. 26-27, and preferably has a viscosity of about 1000 to about 4000 centipoise, preferably about 2000 to about 3000 centipoise. The amount is about 0.25 to 5% by weight, preferably 2.50 to 3.50% by weight, in a mixture of (85 parts) water and (15 parts) glycerin in the gel.

The cellulosic polysaccharide gel carriers of the present invention have been discussed in connection with the preferred sodium carboxymethyl cellulose gel carriers. However, as mentioned above, the tissue enhancing substance is uniformly suspended therein for a substantially infinite period of time and shear thinning (th
Any suitable polysaccharide gel can be used for the carrier of the present invention, as long as it has elasticity and elastic properties. Furthermore, the polysaccharide gel carrier preferably has shear thinning and elastic properties as follows. 1) When a shearing force of 200 Pascal is applied as a stress, it has a viscosity of 1 to 5 million centipoise, and when a shearing force of 500 Pascal is applied as a stress,
It has a viscosity of 300,000 to 1,000,000 centipoise, and 2) the highest external force of 100 Pascal measured at 1 Hertz, and the elastic tensile stress (elastic mo
100% measured at 1 hertz.
With Pascal's highest external force, viscous tensile stress (vis
Cous modulus) is between 0.2 and 1.0, and 4) 10
Strain recovery is 5-7 after applying strain force at 0 Pa for 120 seconds.
5%, 5) most of the strain recovery in 4) above occurs in 2 to 10 seconds. The above measurements can be performed with a stress controlled rheometer. For example, a Hakke RS100 can be used that has 2 cm parallel plates and is capable of stress gradient, vibration, creep, and recovery operations. The actual values for the shear thinning and elasticity properties mentioned above depend on the intended application and the properties of the dispersed particulate (eg size, density, etc.).

Other polysaccharides may also be included or separately used in the tissue enhancing materials and methods of the present invention, such polysaccharides including cellulose, agar, methyl cellulose, hydroxypropyl methyl cellulose, Mention may be made of ethyl cellulose, microcrystalline cellulose, oxidized cellulose, chitin, chitosan, alginic acid, sodium alginate, xanthan gum and other comparable substances.

Unexpectedly, the formulation of the enhanced particles of the present invention, especially calcium hydroxyapatite with sodium carboxymethylcellulose, alters the morphological properties of the surface of the particles. It is believed that such changes can enhance the physical properties and biocompatibility of the substance.

Glycerin in the preferred formulations has several advantages. First, the composition is more lubricious when glycerin is present. Second, for a given level of polysaccharide gel formation, glycerin substantially enhances viscosity compared to pure aqueous gels. Third, the presence of glycerin minimizes gel water loss due to dessication.

Gels have multiple components of the gel at ambient conditions.
preparations) by mixing until all components are in solution. First, glycerin and N 2 until a completely mixed solution is obtained.
It is preferred to combine the aCMC components. Glycerin / NaCMC solution
Then all components are brought into solution and mixed with water until a gel is formed. After the gel components are thoroughly mixed, the gel is left for at least 4 hours. Viscosity measurements are then taken to confirm that the gel has the required viscosity.

Although any lubricant or carrier may be used, certain substances, such as polysorbate surfactants, pectin, chondroitin sulfate, and gelatin,
The ceramic particles cannot be suspended for an indefinite period of time, cannot be subjected to further processing and cannot be easily injected in the same manner as the preferred sodium carboxymethylcellulose. Therefore, sodium carboxymethyl cellulose is preferable.

The preferred polysaccharide gels are biocompatible and maintain the particles of ceramic material in an amount that causes the ceramic particulate / gel composition containing the tissue enhancing material to remain in suspension substantially permanently. It is possible that there is no need to mix before use. As already mentioned, the frictional force caused by the transfer of the enhancing substance by injecting it from the syringe into the tissue site can be reduced by the lubricity of the polysaccharide gel.

In addition, polysaccharides do not have the antigenic response that products containing amino acids have. Such a polysaccharide gel can be immediately sterilized and is stable in ambient conditions. Also, as is done with material systems containing collagen,
There is no need to refrigerate between storage and shipping.

Sterilization is usually carried out by autoclaving at a temperature of about 115 to 130 ° C., preferably at a temperature of 120 to 125 ° C. for about 30 minutes to 1 hour. Gamma irradiation is not suitable for sterilization because it destroys the gel. It has also been found that sterilization usually reduces its viscosity. However, this does not have a detrimental effect on the suspension, so that as long as the gel is kept in the viscosity range mentioned above, the force pushing the enhancing substance out of the syringe will It also does not affect the ability to maintain calcium hydroxyapatite.

After the enhancer has been injected into the tissue, the polysaccharide gel is resorbed harmlessly to the tissue, leaving a matrix of calcium hydroxyapatite that cannot be absorbed in certain areas, or a lump thereof. It has been found that it does not move to other areas of the body. Usually, it takes an average of two weeks for the polysaccharide to be completely absorbed.

FIG. 2 shows the histological site of rabbit 10 tissue magnified 50 times. This is a natural three-dimensional, random-oriented intact soft muscle tissue, 38 ~
It is permeated as a result of the injection of calcium hydroxyapatite having a uniform particle size with a distribution of 63 microns. This micrograph shows the enhancement after 12 weeks. Tissue structure sites also demonstrate the biocompatibility of calcium hydroxyapatite, as multiple cells grow on the surface of the particle with minimal or no substantial external biological response. Is.

The content of calcium hydroxyapatite in the enhancing substance is about 15% to 5%.
0% by volume, preferably about 25% to 47.5%, most preferably
35% to 45% by volume, based on total enhancer including gel and ceramic particles.

Due to the high viscosity of compositions with more than 50% by volume of ceramic particles, the selection of the device for pouring must be done with caution. At a minimum, the enhancer of the present invention must clearly include a sufficient amount of ceramic particles to provide an effective base for endogenous tissue growth. In most applications this is at least 15% by volume. By keeping the volume% around 35 to 45%,
An adjustment factor of about 1: 1 is achieved. That is, the volume of endogenous tissue growth is about the same as the volume of particles introduced and contraction and expansion of the site of soft tissue augmentation generally does not occur.

Also, of these parameters, enhancers can be simply injected intradermally or subcutaneously through a 18 gauge or smaller syringe. The size of the syringe used to introduce or inject the biocompatible enhancer is much smaller due to the reduced frictional force required to deliver it by injecting it into the desired tissue site. can do. This substantially eliminates the possibility of creating needle imprints, which can result in leakage of the enhancer from the injection site after removal of the injection needle. Therefore, the syringe used to inject the enhancer preferably has a reduced size opening, the diameter of the opening being less than 1000 microns, with a minimum value of about 178 microns or less. Is.

For example, an 18 gauge syringe having a diameter of about 838 microns, or about 5
A 20 gauge syringe having a diameter of 84 microns, or a 22 gauge syringe having a diameter of about 406 microns, or a 2 gauge having a diameter of about 178 microns.
An 8 gauge syringe can be used depending on the site where the enhancement material is required.

Lubricating suspensions of the enhancer can be prepared by simply mixing the required amount of ceramic particles with the lubricating gel to form a uniform, homogeneous suspension. it can.

The concentration of ceramic particles suspended in a lubricious gel is comparable to that of strawberry jam, where for all practical applications strawberry seeds and other solids are
Corresponding to ceramic particles, it is maintained in a matrix of jelly-like jam substantially permanently.

Suspensions of ceramic materials in lubricious gels are very stable, centrifugation at a force of the order of 500 g, ie 500 times the force of gravity, generally does not contribute to the stability of the suspension. It has no effect and does not precipitate. The tendency of the particles to settle over a long period of time appears for relatively large particles of 125 microns or larger, if any. Therefore, it is usually not necessary to remix the enhancer at the time of infusion or implantation. In addition, the polysaccharide gel provides lubricity to the suspended ceramic particles so that the force of injection on the syringe is minimized when the enhancer is injected.

The tissue-enhancing substance according to the present invention may be used for treating osteoporosis or conditions related thereto, for example,
It has particular advantages in the treatment of femurs, bone defects resulting from trauma and surgical incisions. The advantages of the substances of the invention in these applications are biocompatibility, ease of application,
Includes excellent results compared to other substances currently used.

In particular, since the enhancing substance can be injected with a fine catheter and needle, it can also be used in incisions smaller than the 4.5 mm hole in the bone, resulting in immediate loss of bone trabeculae. Can be minimized. The opposite of longer-term results than expected. Due to the smaller needle required to use the tissue enhancing substance according to the invention,
The hole diameter is further reduced and its depth is also greatly reduced.

A plurality of particles are kept together by the gel carrier according to the invention for a certain time, even in a liquid environment. At the bone site, the gel provides a means of "fixing" the particles over time.

Furthermore, since the fine particles are relatively small, they are distributed over a wider area through injection at the target site. The viscosity of the gel carrier can be tailored to form a thin, free-flowing density medium, or a thick, strong density, as desired.
This can be done by varying the content of other components of the composition, such as glycerin and sodium carboxymethyl cellulose.

The particle size of the ceramic microparticles in the tissue enhancing material can be reduced for the application. That is, the substance used is fine particles of CaHA of 37 to 63 μm. The advantage of using particles in the relatively large size range in soft tissue is that it ensures that there is no mechanistic migration of cells that may carry the microparticles to sites remote from the tissue. The trigger for this to occur can be greatly reduced, for example, with respect to the fine particles contained in the voids of the columns. Also, the fact that CaHA is known to connect bones further reduces the involvement of migration.

It has also been found that the tissue-enhancing substances of the present invention can be a base for unique substances useful for transplantation applications. In particular, the tissue enhancing substances of the present invention exhibit surprising properties when exposed to air and dried. When extruded from a syringe, either directly or through a needle or catheter, an array of particles with surprising cohesion and flexibility results from exposure to air. The material is substantially anhydrous and it is possible to form the material into various shapes and desired shapes such as sheets. This material can be shaped like clay and can be finished using suitable equipment to prepare a preform for implantation. Advantages of this material include cohesive strength, formability, and high particle concentration per volume unit.

The following examples are illustrative of the present invention. All and percentages are by weight unless otherwise stated.

Examples Example 1 Gel Preparation 3.2% 15% glycerin and 85% (based on total weight of water and glycerin)
5% NaCMC (again based on the sum of the liquid components) is synthesized by the following method. 9.303 g glycerin and 2.016 g NACMC are mixed in a container. The mixture is added slowly with stirring to 52.718 g of water in a batch size vessel and mixed with an electric mixer for 30 minutes at medium speed. The gel is set for a minimum of 4 hours.

Example 2 Preparation of Enhancement Composition Aqueous glycerin / NaCMC gel (44.04 g synthesized in Example 1)
Place in batch size mixing container. Smooth, round and substantially spherical CaHA particles (55.99 g) having a uniform particle size of 75-125 microns were thoroughly mixed for 5 minutes at low speed using an electric mixer and all particles were Evenly distributed in a uniform suspension in. The mixed material is transferred to a 3cc polysulfone cartridge and sterilized by autoclaving at 121 ° C for 60 minutes.

Example 3 Physical Properties of Enhancer Composition The gel synthesized in Example 1 and the enhancer medium synthesized in Example 2 were examined with a parallel plate rheometer (Haake RS100). Tests include the measurement of rheological properties as a function of stress (stress gradient), deformation with constant stress followed by recovery at zero stress (creep / recovery), and within the viscoelastic limit of the composition (frequency sweep). Mention may be made of complex modulus measurements using oscillatory stress. Result is,
The behavior of the gel and the enhancing composition is shown to be the same both before and after sterilization.
For example, this is shown in FIG. FIG. 3 shows the viscosity of the gel and augmented material before and after sterilization as a function of stress from 10 to 1000 Pascals. The shapes of the curves are similar and show the shear thinning properties of this material. Other measurements are shown in the table below. Its viscosity is 500 Pa as measured by stress gradient. The elastic modulus is determined under an oscillating force of 100 Pa at 1 Hertz. Tan δ, which is the ratio of the inelastic modulus to the elastic modulus, is determined under a vibration force of 100 Pa at 1 Hertz. The maximum deflection (deflection) γ _max is a constant 100P.
Determined after 120 seconds at a stress. % Recovery is determined after 120 seconds of constant 100 Pa stress followed by 200 seconds of relaxation.

Table 1. Rheological results of gels and enhancement materials obtained with a 2 cm parallel plate on a Haak RS100 control stress rheometer.

[Table 1]

Example 4 Gel Preparation 25% glycerin, 75% water and 2.25% NaCMC (based on total weight of water and glycerin) are synthesized by the following method. 87.90 g of glycerin and 7.91 g of NACMC are mixed in a vessel large enough to mix the total amount. The mixture is added slowly with stirring to 263.71 g of water in a batch size vessel, at an intermediate speed for 30 minutes,
It is mixed using an electric mixer. The gel is set for a minimum of 4 hours.

Example 5 Preparation of Augmentation Composition Aqueous glycerin / NaCMC gel (38.52 g synthesized in Example 1)
Place in batch size mixing container. Smooth, round and substantially spherical CaHA particles (74.86 g) with a uniform particle size of 37-63 microns were thoroughly mixed for 5 minutes at low speed using an electric mixer, all particles in the gel. Evenly distributed in a uniform suspension of.

Example 6 In most cases there is relatively little resistance, so relatively little force is required to inject or extrude into the air a boosting composition comprising a polysaccharide gel / specific calcium hydroxyapatite. do not do. However, injecting the enhancing composition into tissue requires more force, which is greatly affected by the geometry of the particular material. This is 7
A sterilized suspension of a polysaccharide gel consisting of 5% water, 25% glycerin and 2.25% sodium carboxymethylcellulose (based on the total weight of water and glycerin) was made into different shapes according to the procedure of Example 2. It was demonstrated by synthesizing with various volume% of calcium hydroxyapatite having. The suspension thus synthesized was placed in a standard 3 cm ³ syringe. The force on the plunger was measured to force the polysaccharide gel / specific suspension through an 18 gauge needle at a rate of 1 inch per minute. Its power is similar to clinical use, with turkey gizzard (
gizzard) was also measured with a needle injected into the tissue. The spray-dried particles of calcium hydroxyapatite, regardless of their shape, had a smooth, uniform appearance under 40x microscope observation. The particles were evenly distributed within the size range. The results are shown in Table 2.

[0103]

[Table 2]

This data correlated with animal studies where irregular particles could not be injected into tissue even if solids were reduced to less than 25% or a 16 gauge needle was used.

Example 7 A sterilized sample of a polysaccharide gel / specific calcium hydroxyapatite suspension was
Prepared using a range of specified particle size ranges. The distribution of particles was uniform within each particle size. The particles are smooth, round calcium hydroxyapatite and the gel has the same substrate as in Example 1. Calcium hydroxyapatite particles accounted for 36% by volume of the suspension. The force for pushing each suspension, each containing a particle size in the specified range, into the air was measured using a 3 cm ³ syringe as in Example 6. The results are shown in Table 3. Table 3 shows that as the particle size increases, the extrusion force makes little difference as long as the particle size is uniform and maintained in a narrow distribution.

[0106]

[Table 3]

Example 8 Sodium carboxymethyl cellulose, water and glycerin at various weight percentages were
It was formulated into 4 different gels as in Example 1 except the use of different ratios. Each gel was mixed with about 40% by volume calcium hydroxyapatite particles having a distribution of 38-63 microns. The gel / particle mixture was placed in a standard 3 cm ³ syringe fitted with an 18 gauge, 20 gauge, 22 gauge needle. The pushing force of the mixture into the air was measured as in Example 3.
The results are shown in Table 4.

[0108]

[Table 4]

Example 9 Preparation of Enhancement Composition Use of Polystyrene Microbeads A gel consisting of 4.93% glycerin, 93.60% water and 1.48% NaCMC was prepared according to the method described in Example 1. Was prepared. Spherical polystyrene beads (12.79 g) with a particle size range of 100-500 microns are run at low speed for 5 minutes,
Mix well with an electric planetary mixer and all particles are evenly distributed in a uniform suspension in 28.43 g of gel. The polystyrene beads have a density of 1.07 g / cc as measured by a helium pycnometer. The mixed material is placed in a 10 cc polypropylene syringe cartridge and sterilized in an autoclave at 121 ° C. for 60 minutes. The polystyrene beads remain evenly distributed within the gel carrier. Rheological properties were measured as described in Example 3. Its viscosity is determined at 100 Pa by stress gradient measurement. Its viscoelastic modulus is 1
It is determined under a vibration force of 20 Pa in Hertz. Tan δ, which is the ratio of the inelastic modulus to the elastic modulus, is determined under a vibration force of 20 Pa at 1 Hertz. Its maximum deflection γ _max is determined after 120 seconds at a constant 10 Pa stress. % Recovery is determined after 120 seconds of constant 10 Pa stress followed by 200 seconds of relaxation. The results are shown in Table 5.

Table 5. Rheological results of gel and polystyrene enhancing materials obtained with a 2 cm parallel plate on a Haak RS100 control stress rheometer.

[Table 5]

Example 10 Preparation of Enhancement Composition Use of Polymethyl Methacrylate Microbeads 9.80% Glycerin, 88.24% Water and 1.96% NaCMC were prepared by the method described in Example 1. Was done. Spherical polymethylmethacrylate beads (12.78 g) with uniform particle size 100-180 micron were mixed well in an electric planetary mixer for 5 minutes at low speed, all particles in 28.84 g gel. Evenly distributed in a uniform suspension of. The polymethylmethacrylate beads have a density of 1.21 g / cc as measured by a helium pycnometer. Mixed material is 10c
c Place in polypropylene syringe cartridge and sterilize in autoclave for 60 minutes at 121 ° C. The polymethylmethacrylate beads remain evenly distributed within the gel carrier. Rheological properties were measured as described in Example 6. Its viscosity is determined at 100 Pa by stress gradient measurement. Its viscoelastic modulus is determined under an oscillating force of 20 Pa at 1 Hertz. The ratio of the inelastic modulus to the elastic modulus, tan δ, is determined under the vibration force of Pa at 1 hertz. The maximum deflection γ _max is determined after 120 seconds at a constant 20 Pa stress. % Recovery is determined after 120 seconds of constant 20 Pa stress followed by 200 seconds of relaxation. The results are shown in Table 6.

Table 6. Rheological results of gel and polymethylmethacrylate enhancing materials obtained with a 2 cm parallel plate on a Haak RS100 control stress rheometer.

[Table 6]

Example 11 Preparation of Enhancement Composition Use of Glass Microbeads 14.56% Glycerin, 82.52% Water and 2.91% NaCMC were prepared by the method described in Example 1. Spherical glass beads (30.42 g) with a uniform particle size of 30-90 micron were mixed well in an electric planetary mixer for 5 minutes at low speed, all particles were homogeneous in 29.27 g gel. Evenly distributed in suspension. Glass beads have a density of 2.5 as measured by a helium pycnometer.
It has 4 g / cc. The mixed material is placed in a 10 cc polypropylene syringe cartridge and sterilized in an autoclave at 121 ° C. for 60 minutes. The glass beads remain evenly distributed within the gel carrier. Rheological properties were measured as described in Example 3. Its viscosity is 500 Pa as measured by a stress gradient.
Is determined by. Its viscoelastic modulus is determined under an oscillating force of 100 Pa at 1 Hertz. Tan δ, which is the ratio of the inelastic modulus to the elastic modulus, is determined under a vibration force of 100 Pa at 1 Hertz. Its maximum deflection γ _max is determined after 120 seconds at a constant 100 Pa stress. % Recovery is determined after 120 seconds of constant 100 Pa stress followed by 200 seconds of relaxation. The results are shown in Table 7. The sterilized augmentation material was filled into a 3cc syringe cartridge,
Extruded through a 3.5 inch gauge spinal needle. The average extrusion force was 14.63 Lbs with a standard deviation of 0.09 Lbs.

Table 7. Rheological results of gel and glass enhancing materials obtained with a 2 cm parallel plate on a Haak RS100 control stress rheometer.

[Table 7]

Example 12 Preparation of Enhancement Composition Use of Stainless Steel Microbeads 4.76% Glycerin, 90.48% Water and 4.76% NaCMC were prepared by the method described in Example 1. . The mixing time was extended from 30 minutes to 1 hour for this formulation. Spherical stainless steel beads (95.19 g) with uniform particle size 60-125 micron were mixed well in an electric planetary mixer for 5 minutes at low speed, all particles were homogeneous in 28.69 g gel. Evenly distributed in different suspensions. Stainless steel beads have a density of 7.93 g / cc as measured by a helium pycnometer. The mixed material is placed in a 10 cc polypropylene syringe cartridge and sterilized in an autoclave at 121 ° C. for 60 minutes. The stainless steel beads remain evenly distributed within the gel carrier. Rheological properties were measured as described in Example 3. Its viscosity is determined at 500 Pa by stress gradient measurement. Its viscoelastic modulus is
Determined under a vibrational force of 100 Pa at 1 Hertz. The ratio of the inelastic modulus to the elastic modulus, tan δ, is determined under a vibration force of 100 Pa at 1 Hertz. The maximum deflection (deflection) γ _max is 1 at a constant 100 Pa stress.
Determined after 20 seconds. % Recovery lasts 120 seconds at constant 100 Pa stress 2
After relaxation for 00 seconds, it is determined. The results are shown in Table 8. 3 sterilized augmentation materials
It was loaded into a cc syringe cartridge and extruded through a 3.5 inch 20 gauge spinal needle. The average extrusion force has a standard deviation of 0.37 Lbs and is 30
． It was 84 Lbs.

Table 8. Rheological results of gel and stainless steel augmented materials obtained with a 2 cm parallel plate on a Haak RS100 control stress rheometer.

[Table 8]

Example 13 Use of a xanthan gum gel former 13.8 parts glycerin, 78.2 parts water and 8 parts xanthan polysaccharide were prepared by the method described in Example 1. The viscosity of the gel was 51,250 cps, measured using a Brookfield Rheometer. Calcium hydroxyapatite particles, which range in diameter from 75 to 125 microns, are mixed well in an electric planetary mixer at low speed for 5 minutes so that all particles are evenly distributed in a uniform suspension in the gel. The mixed material is placed in a polypropylene syringe cartridge and sterilized in an autoclave at 121 ° C for 60 minutes. The hydroxyapatite particles remain uniformly distributed within the gel carrier. Centrifuging the cartridge for 5 minutes at 106 × g force using an IEC clinical centrifuge, model OM428, did not result in particle settling within the gel carrier. (This result is
It suggests that the particles will not settle over an extended period of time as the elastic limit of the gel is not exceeded. ) The augmentation material is 1.5 from the syringe cartridge.
Extruded through an inch 18 gauge needle. The required force is 3.90 Lbs
Met.

Example 14 Use of Xanthum Gel-Forming Agent and Isopropyl Alcohol 64.4 parts of isopropyl alcohol, 27.6 parts of water and 8 parts of xantham polysaccharide were prepared by the method described in Example 1. The viscosity of the gel was 37,500 cps, measured using a Brookfield Rheometer. Diameter 7
Calcium hydroxyapatite particles, which range from 5 to 125 microns, are mixed well in an electric planetary mixer for 5 minutes at low speed, so that all particles are evenly distributed in a uniform suspension in the gel. The mixed material is placed in a polypropylene syringe cartridge and sterilized in an autoclave at 121 ° C for 60 minutes. The hydroxyapatite particles remain uniformly distributed within the gel carrier. IE
Centrifugation of the cartridge with a C clinical centrifuge, model OM428 at 1016 × g for 5 minutes did not result in particle settling within the gel carrier.
(This result suggests that the particles will not settle over an extended period of time because they do not exceed the elastic limit of the gel.) The augmented material was passed from a syringe cartridge through a 1.5 inch 18 gauge needle. Was pushed out. The required power is
It was 7.34 Lbs.

Example 15 A gel is prepared according to Example 1 and an augmentation medium is prepared according to Example 2. The patient is appropriately anesthetized and a hole (larger than 18 gauge needle) is drilled in the femoral neck, head and trochanteric area at the entrance of the soft cancellous portion of the larger trochanter. . A 3.5 inch long 18 gauge needle is connected to the syringe containing the augmentation medium using a Luer lock connection. The augmentation medium is injected into the bone through the hole. Injecting sufficient material between the particles to serve as a skeleton for bone growth, forming bone, strengthening the trochanter of the femur and the femoral head, reducing the risk of fracture.

Although the present invention has been described with reference to preferred embodiments, many other variations and modifications and other uses will become apparent to those skilled in the art without departing from the scope of the invention. Let's Therefore, preferably, the invention is not limited to the specific disclosure herein, but only by the appended claims.

[Brief description of drawings]

FIG. 1 is a micrograph of smooth round hydroxyapatite calcium particles at 40 × magnification.

FIG. 2 is a micrograph of a tissue section of rabbit tissue at 50 × magnification showing fibroblast infiltration.

[Figure 3]   It is a graph of the viscosity of the gel before and behind sterilization, and an augmentation medium.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 47/10 A61K 47/10 47/38 47/38 A61L 27/00 A61L 27/00 F U V (81 ) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF) , CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG) , ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, B , BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL , PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Divine, Timothy Earl 53217, Wisconsin, USA Whitefish Bay, North Woodbury Street 4819 F-term (reference) 4C076 AA09 BB32 CC09 DD37 DD38 EE30 EE31 EE32 EE33 EE36 EE37 EE38 FF35 4C081 AB02 AB11 AB18 BA13 CA01 CF03 CF01 CF02 CF02 CF02 CF02 CF02 1 DA12 4C086 AA02 FA10 HA04 HA05 HA16 HA18 HA19 HA23 HA24 HA30 MA02 MA05 MA27 MA67 NA10 ZA31 ZA94 ZA96

Claims (56)

[Claims] 1. A biocompatible, absorbable and lubricious material for suspending a biomaterial in a tissue enhancing substance comprising a polysaccharide gel having a viscosity of 200,000 to about 350,000 centipoise or higher. A carrier, wherein the polysaccharide gel retains the biomaterial uniformly suspended in the tissue enhancing substance prior to and at the time of introducing the tissue enhancing substance to the desired tissue site. A carrier characterized by the following. 2. The carrier according to claim 1, wherein the polysaccharide gel is an aqueous polysaccharide gel. 3. A polysaccharide gel comprising cellulose polysaccharide, starch, chitin, chitosan, hyaluronic acid, polysaccharide modified with a hydrophobic substance, alginic acid, carrageenan, agar, agarose, intramolecular complex of polysaccharide, oligosaccharide, and large sugar The carrier according to claim 1, comprising a polysaccharide selected from the group consisting of cyclic polysaccharides. 4. The carrier according to claim 3, wherein the polysaccharide gel contains a cellulose polysaccharide. 5. The carrier according to claim 4, wherein the cellulose polysaccharide is selected from the group consisting of sodium carboxymethyl cellulose, methyl cellulose agar, methyl cellulose hydroxypropyl, ethyl cellulose, microcrystalline cellulose, and oxidized cellulose. 6. The carrier according to claim 5, wherein the cellulose polysaccharide is sodium carboxymethyl cellulose. 7. The carrier according to claim 1, wherein the polysaccharide gel contains a solvent selected from the group consisting of water and aqueous alcohol. 8. The carrier according to 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. 9. The carrier according to claim 2, further comprising glycerin. 10. The carrier according to claim 9, wherein water and glycerin are present in the aqueous polysaccharide gel in a ratio of about 20:80 to 90:10. 11. The carrier according to claim 10, wherein water and glycerin are present in the gel in a ratio of 85:15. 12. The carrier according to claim 1, wherein the biomaterial is selected from the group consisting of ceramics, plastics and metals. 13. The carrier according to claim 12, wherein the biomaterial is ceramic. 14. The carrier of claim 13 wherein the ceramic is rounded, substantially spherical, biocompatible, substantially non-resorbable and comprises finely divided ceramic particles. 15. The carrier according to 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 ceramic particles are calcium phosphate particles.
5. The carrier according to item 5. 17. Calcium phosphate particles are hydroxyapatite calcium particles, tetracalcium phosphate particles, calcium pyrophosphate particles, tricalcium phosphate particles, octacalcium phosphate particles, fluoroapatite calcium particles,
The carrier according to claim 16, which is selected from the group consisting of calcium carbonate apatite particles, and a mixture thereof. 18. The carrier according to claim 17, wherein the calcium phosphate particles are hydroxyapatite calcium particles. 19. The carrier according to claim 1, wherein the desired tissue site is a bone site. 20. The carrier according to claim 19, wherein the desired tissue site is a site of osteoporotic bone. 21. A biocompatibility for tissue augmentation comprising a biomaterial for augmenting a desired tissue site and a carrier for the biocompatible, absorbable lubricious biomaterial. A composition, wherein the carrier comprises 200,000 to about 350,00.
A polysaccharide gel having a viscosity of 0 centipoise or greater and uniformly suspended in the biocompatible composition prior to enhancement of the desired tissue site and during introduction of the biocompatible composition to the desired tissue site. A biocompatible composition, characterized in that it retains a biomaterial. 22. The composition according to claim 21, wherein the polysaccharide gel is an aqueous polysaccharide gel. 23. A polysaccharide gel comprising a cellulose polysaccharide, starch, chitin, chitosan, hyaluronic acid, a polysaccharide modified with a hydrophobic substance, alginic acid, carrageenan, agar, agarose, an intramolecular complex of a polysaccharide, an oligosaccharide, and a large sugar. 22. The composition of claim 21, comprising a polysaccharide selected from the group consisting of cyclic polysaccharides. 24. The composition of claim 23, wherein the polysaccharide gel comprises a cellulose polysaccharide. 25. The composition of claim 24, wherein the cellulosic polysaccharide is selected from the group consisting of sodium carboxymethyl cellulose, methyl cellulose agar, methyl cellulose hydroxypropyl, ethyl cellulose, microcrystalline cellulose, and oxidized cellulose. 26. The composition of claim 25, wherein the cellulose polysaccharide is sodium carboxymethyl cellulose. 27. The composition according to 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. 29. The composition of claim 22, further comprising glycerin. 30. The composition of claim 29, wherein water and glycerin are present in the aqueous polysaccharide gel in a ratio of about 20:80 to 90:10. 31. The composition of claim 30, wherein water and glycerin are present in the aqueous polysaccharide gel in a ratio of 85:15. 32. 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 rounded, substantially spherical, biocompatible, substantially non-absorbable, 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 ceramic particles are calcium phosphate particles.
The composition according to 5. 37. Calcium phosphate particles are hydroxyapatite calcium particles, tetracalcium phosphate particles, calcium pyrophosphate particles, tricalcium phosphate particles, octacalcium phosphate particles, fluoroapatite calcium particles,
37. The composition of claim 36, selected from the group consisting of calcium carbonate apatite particles, and mixtures thereof. 38. The composition according to claim 37, wherein the calcium phosphate particles are hydroxyapatite calcium particles. 39. 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 site of osteoporotic bone. 41. Biocompatibility for tissue augmentation, comprising biomaterial for augmenting a desired tissue site and a carrier for biocompatible, absorbable lubricious biomaterial. In the composition, the biocompatible composition having a viscosity of 200,000 to about 350,000 centipoise or higher, prior to the enhancement of the desired tissue site and during the introduction of the biocompatible composition to the desired tissue site. An improvement comprising a polysaccharide gel carrier which holds a biomaterial uniformly suspended in a product. 42. A biomaterial for enhancing a desired tissue site, dehydrated,
A suspension medium for a biocompatible absorbable biomaterial comprising a dehydrated polysaccharide gel for retaining the biomaterial suspended in an implant composition. , A substantially dehydrated biocompatible composition. 43. The composition of claim 42 formed into a preform for implantation at a desired tissue site. 44. A polysaccharide gel comprising a cellulose polysaccharide, starch, chitin, chitosan, hyaluronic acid, a hydrophobic substance-modified polysaccharide, alginic acid, carrageenan, agar, agarose, an intramolecular complex of a polysaccharide, an oligosaccharide, and a large sugar. 43. The composition of claim 42, which comprises a polysaccharide selected from the group consisting of cyclic polysaccharides. 45. The composition of claim 44, wherein the polysaccharide gel comprises a cellulosic polysaccharide. 46. The composition of claim 45, wherein the cellulosic polysaccharide is selected from the group consisting of sodium carboxymethylcellulose, methylcellulose agar, methylcellulose hydroxypropyl, ethylcellulose, microcrystalline cellulose, and oxidized cellulose. 47. The composition of claim 46, wherein the cellulose polysaccharide is sodium carboxymethyl cellulose. 48. 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 rounded, substantially spherical, biocompatible, substantially non-absorbable, 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 ceramic particles are calcium phosphate particles.
The composition according to 1. 53. Calcium phosphate particles are hydroxyapatite calcium particles, tetracalcium phosphate particles, calcium pyrophosphate particles, tricalcium phosphate particles, octacalcium phosphate particles, fluoroapatite calcium particles,
53. The composition of claim 52 selected from the group consisting of calcium carbonate apatite particles, and mixtures thereof. 54. The composition according to claim 53, wherein the calcium phosphate particles are hydroxyapatite calcium particles. 55. A method of making a substantially dehydrated biocompatible composition for implantation at a desired tissue site, the biomaterial being for enhancing the desired tissue site, and being biocompatible. A carrier for an absorbable, lubricious biomaterial, the carrier comprising a polysaccharide gel having a viscosity of 200,000 to about 350,000 centipoise or higher. A method including the step of causing. 56. The method of claim 55, further comprising molding the substantially dehydrated biocompatible composition into a preform for implantation at a desired tissue site.