Bioactive granules for bone tissue formation

Bioactive granules for tissue formation osseous.

Technical field

The present invention relates to materials of bioactive glass implant.

Background of the invention

The biocompatibility of bioactive glasses, as manifested by the tight apposition of hard tissue to the implanted vitreous particles have been continuously demonstrated since 1971. Specifically, the composition of one of these glasses Bioactive, 45S5 Bioglass®, was originally presented by Hench<i>et al</i>., <i>J. Biomed. Mater. Res. Symp.,</i>2: 117-141 (1971). The nature of the interface Glass / bone tissue has been discussed in terms of formation of a reactive region on the glass surface. It was established that the ionic exchange between extracellular fluid and glass on the surface it transforms the silica constituent of the glass into a gel while increasing the pH of the surrounding medium local. Simultaneously, a thin layer of calcium phosphate is formed in the outer surface of the glass transmitted through the cellular activity The bone grows by apposition on the glass bioactive placed adjacent to bone surfaces and the new bone can be directed later, over distances short In the event that the bioactive glass has the form of granules, the new bone can be directed from granule in granule.

The granules of bioactive glass U.S. Patent No. 4,239,113 describes a composition for the preparation of bone cement. He cement has an inorganic part that comprises between 15 and 75% by weight of cement. The inorganic part also contains powder bioactive glass ceramic that has a particle size of 10-200 micrometers in a part of the 90-99% by weight and between 1 and 10% of fibers vitreous minerals by weight. The composition of bone cement contains also a mixture of methyl methacrylate and methyl methacrylate copolymers, a catalyst of healing, and preferably an accelerator.

U.S. Patent No. 4,851,046 describes compositions containing 45S5 particles Bioglass®, of various size ranges for use in periodontal applications. It has been claimed that particles with a wider range of sizes can produce a clinically mixed more desirable A range of particle sizes of 90-710 micrometers has been described so specific as being the most effective. The glass powders are they mixed well with the blood and formed a cohesive mixture that He also stopped the bleeding.

U.S. Patent No. 5,204,106, to Schepers favor, <i>et al</i>., April 20, 1993 (incorporated herein by reference), reveals that the particles of bioactive glass having the composition of 45S5 within the range narrow sizes from 280 to 425 micrometers (\ mum) cause a biological response clearly altered with respect to that described previously. The particles within this specific range of sizes were implanted in the jaw bone of adult dogs young and disintegrated from the inside, that is, they they excavated, disappeared, and were gradually replaced and quickly by bone tissue rather than fibrous tissue. It is revealed that, as the particles disintegrate, the interior constitutes a highly protected medium that makes it possible to create and maintain favorable conditions for cell differentiation mesenchymal in osteoblasts. When particles were implanted from 45S5 bioactive glass outside the specific range of sizes, it is not however, he observed no excavation. With larger particles (it is say, 425-850 \ mum), there was no central disintegration with resorption or dissolution of the glass and bone tissue replacement. External growth of the bone tissue by osteoconduction from the wall of the cavity, but the particles in the center of the cavity were surrounded by tissue fibrous. With smaller particles (i.e. 212-300 µm), osteoconduction was observed from the wall of the cavity, but, again, the particles in the center they were surrounded by fibrous tissue, before disappearing under the action of phagocyte cells.

The particles that Schepers reveals <i>et al</i>., They have also been used in successful orthopedic situations. Specifically, particles were implanted in the range of 300 to 355 um inside the ankle of a patient to fill the gaps of the screws when removing the plate from a bone. The treatment Complementary x-ray revealed that the granules stimulated the bone tissue formation.

It is notable as the bone formation observed in Schepers <i>et al</i>. takes place throughout the defective part by Osteo-stimulation osteogenesis medium, assisted by osteoconduction due to the calcium phosphate layer that forms before centrally decayed, cellularly transmitted. To central disintegration, bioactive glass particles are They completely transform into calcium phosphate. The composition and the size of the preferred granules in the Schepers patent <i>et to the</i>. they are such that the particles gradually transform already that the defective part becomes vascularized and populated with bone tissue forming cells. The smallest particles reacted too quickly, generating an inflammatory response acute, thereby preventing the formation of bone tissue.

The material described in the Schepers patent<i>et al</i>., is suitable for many cases of repair of defects where particles with increased capacity of Bone tissue formation are not necessary. However, it continues There is a need for a material with greater reactivity in Some defect repair applications. These cases are described in more detail below.

Summary of the invention

It was desired to expand the range of sizes of Useful particles for bioactive granules. The most particles small accelerate bone repair by providing more nuclei for the formation of bone tissue. Also, if the reactions of corrosion and resorption could be controlled so that there was no acute inflammatory response reactions caused by interference with the formation of bone tissue, a faster repair of the defective part. By recognizing that the jaw is in an area with intensified circulation of liquids, that is to say in an area above the neck, was considered that the abundance of interstitial fluids and the circulation of enriched blood in these areas, along with bioactivity increased from the smallest particles, they had contributed to the incomplete results previously observed for smaller granules. In addition, it was understood that the metabolic rate rigorous in young adult dogs had contributed to the intensified inflammatory response previously observed with smaller particles .

In one aspect, the present invention relates to a method to form bone tissue at an orthopedic site in an area with reduced metabolic state which comprises the implantation of bioactive glass particles located in a range sizes from 200 to 300 micrometers.

The orthopedic site can be located in the appendicular skeleton. The appendicular skeleton as described in <i>Principles of Human Anatomy</i>, Gerard J. Tortora, ed., Pp. 92-204, Harper &amp; Row, New York, (1983) (incorporated here as a reference) includes the shoulder girdle (clavicle and shoulder blade); the upper extremities (humerus, cube, radio, carpus, metacarpus and phalanges); pelvic girdle (bone pelvic); and the lower extremities (femur, fibula, tibia, patella, tarsus, metatarsus and phalanges). How will a art specialist, the appendicular skeleton does not experience generally no intensified fluid circulation observed in the skull-facial skeleton. The term "appendicular skeleton", as used herein, includes the comparable regions in animals.

Metabolic states are influenced by the age and genetic disposition of a subject. For example, him "reduced metabolic state" is observed in subjects with osteoporosis. The reduced metabolic states are observed generally also in the elderly. The term "major" as defined here, includes people of 60 years and more, although there may be exceptions. There will also be others situations in which a reduced metabolic state is shown, that the present invention encompasses. Although some may be done diagnostic tests to show metabolic status reduced, the evaluation is not totally empirical. However, the Art specialists can perform an evaluation easily. It will be appreciated that the method according to the invention can be used at any bone site in a metabolic state reduced.

It is proposed that there are sites with intermediate circulation of fluids and metabolism, or an evolution of these locations, for which it is desirable to have a implant material according to the invention. In addition, the regions generally considered to have the characteristics of an intensified circulation of fluids and metabolism may not show these characteristics in certain circumstances, or in Some disease states. In this case, the implementation of the granules according to the present invention would be appropriate in this region, even if it is in the area cranio-facial as described previously.

Bone defects raised include, but not are limited to the following: cystic defect repairs, sites of benign and malignant tumors upon resection, bone loss, fracture repair sites even late- or non-binding sites, joint repair sites, defects related to osteoporosis, and periodontal defects.

The compositions and methods described here may be used in veterinary and human applications.

Brief description of the drawings

Figure 1 describes the excavation observed with 45S5 glass granules.

Figure 2 describes the excavation observed with Granules with glass composition Gl.

Detailed description

The method according to the invention refers to to the implantation of bioactive glass granules in the range of sizes from about 200 to about 300 micrometers Bioactive glass granules contain oxides of silicon, sodium, calcium, and phosphorus in the following percentages in weight: from 40 to 58% of SiO2, from 10 to 30% of Na2O, from 10 to 30% of CaO, and from 0 to 10% of P 2 O 5. In one embodiment preferred, the composition of the bioactive glass granules is of the 45% SiO2, 24.5% Na2O, 24.5% CaO, and 6% of P 2 O 5. In another preferred embodiment, the composition of The bioactive glass granules is 52% SiO2, 21% of Na 2 O, 21% CaO, and 6% P 2 P 5.

In previous studies using of 45S5 bioactive glass particles whose size ranged from 212 and 300 micrometers, no excavation occurred. The term "excavation" is defined as the formation of a central cavity in the inside of the particle at the time of the complete reaction of the particle that includes gelation and layer formation of calcium phosphate. Subsequently, osteoprogenitor cells, including mesenchymal cells, penetrate the cavity and they differ in bone formation cells. Thus, the bone tissue is Osteostimulation form from within the defect. The excavation it is evident when observing the cells within a particle that Have a defined edge.

One reason why excavation may not having previously been done with smaller particles is the abundant corrosion reaction of these particles in a site with intensified circulation of liquids and with a vigorous metabolic state. This led to an answer. acute inflammatory Generally, the corrosion reaction continues at increased speeds with an increased surface area and, concomitantly, a reduced particle diameter. In consequently, it was thought that bioactive glass particles with a size range from about 200 to about 300 micrometers may be too reactive in some regions with intensified circulation of liquids. It was expected that, even in sites that did not have an intensified circulation of liquids, some modification of the composition would be necessary to observe the excavation with smaller particles.

Granules were prepared specifically of bioactive glass particles whose size range is was between about 200 and about 300 microns that had four different glass compositions. Granules were prepared by using the process derived from the fusion and crushing described previously in the Patent of the United States No. 5,204,106, whose discovery is incorporated herein as reference. However, they are expected to be also Suitable granules prepared by other processes.

The four different compositions used They are listed below in Table I. The first composition represents that of the bioactive glass designated by 45S5. GI to GIII they represent the modifications of the glass composition.

TABLE I

<figref>1</figref>

Implantation was performed on defects created in The ilium of rabbits. The ilium has a limited spongy bone, therefore, defects are not quickly repaired by new bone growth Also, the ilion is not in a site with intensified circulation of liquids. Thus He chose the ilium as a location for implantation. The rabbits they were chosen as an accepted animal model to study the response to materials both for veterinary use As for your human use.

Unexpectedly, it was discovered that particles that had the composition 45S5 whose size range is was between 200 and 300 micrometers, they were digging at Four weeks of implantation. Osteoconduction was observed extensive with direct union of bone to particles in association with the excavation of the particles. The evidence was also observed of compositional changes and excavation with composition GI; they are also found by all these large defective parts bone amounts

Example 1

200 granules were implanted in the rabbits at 300 micrometers that had the compositions contained in the Table I. The four compositions were implanted to each rabbit. He placed two circular defects of three millimeters (mm) of diameter about 15 mm center points in each ilium of the New Zealand white rabbits. Sequentially expanded defects in three phases up to a final diameter of 8 mm and filled with glass granules (200-300 µm) that had one of the compositions indicated in Table I. implanted in each defect a material of unique composition. The Placement was random. The rabbits were sacrificed four weeks after implantation for recognition histological repair.

Block sections of the ilions and immersed in polymethyl methacrylate. Five consecutive sections of each defect were obtained, close to a diameter Three sections were colored - each one with trichrome which is generally used to observe cell detail; Giemsa, which is used to contrast bone and fibrous tissue; and Paragon, which is used to contrast bone and fibrous tissue and the glass, and for the cellular detail.

Histological observations from three Rabbits are presented in Table II below. In the table, "RC", "RA", "LC", and "LA" represent respectively the caudal and cephalic defects of the right and of the left. "Flow" refers to the defect positioned more towards the back of the animal. "Cephalic" refers to defect positioned more towards the head. The "Group" numbers correspond to those listed in Table I. "Excavation" has been described above. "Composition changes" are those changes in color and hue of the particles that are They can observe when they are colored. This is indicative of the glass corrosion reactions that lead to changes in the chemical composition of the granulated material. "Bone filling" is defined in terms of repair of the individual defect. This can take place as a normal repairing process and therefore I don't know It is necessarily due to the use of the material itself. No this related to the comparison with a control. "Disintegration of Macrophages "refers to the observation of cells phagocytic very close to the outside of the granules: These cells cause the scalloped appearance of some granules. The scale is as follows: "ND" indicates that no attempt was made remark, "-" indicates that the element was not observed, "+" indicates that the item was found, "++" indicates that much of the element was observed, "+++" indicates that the element was observed extensively.

In the case of the 45S5 composition of the range of specified sizes, the particles reacted fully with the visible evidence of core excavation. This is described. in Figure 1. Figure 1 represents the tissue from the Rabbit 12RA colored with trichrome and seen with increase of 100 diameters The excavation is indicated with the arrows.

The reaction layer associated with the granules of GI extended approximately midway within the centers at four weeks; the particles did not react completely in this period of time, but the excavation progressed. This is coming represented in Figure 2. Figure 2 represents the fabric from Rabbit 9LA colored with trichrome and seen with magnification 100 diameters The excavation region in progress is indicated by the arrow.

The particles of the GII composition had a very thin reaction layer that looked as if was eaten by moths due to the resorption of surface macrophages in certain areas. The use of GII particles resulted in an abundance of macrophages very close of the granules and in the absence of major changes of the surface composition. In the case of GII materials and GIII, less apposition of the bone to the granules of glass.

The foregoing was intended to illustrate the invention and does not limit it in any way. The art specialists will recognize that they can be done modifications, what lies within the spirit and the scope of the invention as defined in the claims attached.

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TABLE II

<figref>2</figref>