RU2793324C1 - Nanodispersed plastic bioengineering composition based on cerium dioxide for replenishing the volume of bone tissue - Google Patents

Abstract

FIELD medicine; dentistry.

SUBSTANCE: invention can be used in osteoplastic surgery of jaw bone tissue defects during dental implantation, as well as in periodontal reconstructive surgery and guided bone regeneration to replenish bone tissue volume. A plastic bioengineering composition for replenishing the volume of bone tissue in the maxillofacial area includes a mixture of granular xenogenic or synthetic filler with a fibrin clot L-PRF with a particle size of 0.25–1.00 mm and a suspension of PRP from the patient's plasma with nanodispersed cerium dioxide in physiological saline at a concentration of 10^-5 M at a ratio of 2:1, and the ratio of the components of the filler composition (g): L-PRF (g): PRP with nanosized cerium dioxide (ml) is 1:4:2.

EFFECT: invention provides for the creation of a plastic bioresorbable composition with a targeted stimulating effect that affects the proliferation of osteoblasts, reduces atrophic processes, preserves the structure of the mucous membrane, minimizes inflammatory complications in the postoperative period, achieves more reliable isolation of the bone wound from the negative effects of the contents of the oral cavity, including pathogenic infection.

1 cl, 2 dwg, 1 tbl, 2 ex

Description

SUBSTANCE: invention relates to medicine, namely to dentistry, and can be used in osteoplastic surgery of jaw bone tissue defects during dental implantation, as well as in periodontal reconstructive surgery and guided bone regeneration to replenish bone tissue volume.

Bone tissue defects can occur after dental surgeries and their complications, as well as as a result of chronic destructive processes.

Relevant is the search for methods of filling the missing volume of bone tissue, associated with minimal invasion, as well as the possibility of filling defects immediately after tooth extraction or during guided bone regeneration. In addition, it is necessary that the bioconstruct has a directed stimulating effect on regeneration processes.

The use of PRF-blood clots saturated with growth factors for osteo- and angiogenesis makes it possible to partially solve this problem. At the same time, such PRF-clots do not have sufficient stability, quickly disintegrate and diffuse into soft tissues. As a rule, such clots are used as membranes for closing defects filled with osteoplastic material in order to saturate it and the edges of the defect with growth factors and accelerate regeneration.

Recently, in the treatment of periodontal diseases, PRP-plasma, platelet-rich autoplasma in the liquid phase, has been used. Platelets contain specific protein compounds - growth factors, which are biologically active polypeptide molecules that activate receptors on the cell surface, which, in turn, starts the process of tissue regeneration. Platelet autologous plasma (TAP) is a highly active biological stimulator of regeneration processes due to various growth factors contained in platelet alpha granules, which act on all structural units of surrounding tissues and stimulate regeneration processes. The reason for the use of autologous platelet-rich plasma was the discovery that platelets contain protein factors (PRP-factors) that initiate the cellular regenerative process.

The liquid phase of the plasma itself can only be injected into tissues. Ultimately, this technique is applicable only to soft tissues, and only indirectly to bone tissue.

To obtain a stable structure to fill bone defects and, at the same time, saturated with platelet growth factors, as well as other non-specific stimulators of osteogenesis and angiogenesis, it is necessary to use them on a carrier. Such a filler can be granular osteoplastic material of various origins - xenogenic, synthetic.

An additional stimulating factor can be the introduction of nanodispersed cerium dioxide into the structure. The specific ability of nanosized cerium dioxide to regenerate is an extremely important property of this material. Nanodispersed CeO2 is able to imitate the properties of a number of enzymes. Its regenerative behavior also provides enzyme-like activity. The ability of nanodispersed cerium dioxide to perform the functions of enzymes is an undoubted prospect for the relief of various pathological processes associated primarily with oxidative stress. Thus, cerium dioxide nanoparticles accelerate wound healing by reducing oxidative damage to membranes and proteins, increase the proliferation and migration of fibroblasts, keratinocytes, and vascular endothelial cells.

As a result of the conducted information and patent search, the following patents were selected for further analysis.

Known material for implantation and periodontal plastics, which contains platelet-rich autoplasma of the patient, titanium nickelide powder with particle sizes up to 100 nm, colloidal 2.5% nanostructured silver with particle sizes up to 20 nm. A method for obtaining a material is proposed, which consists in the fact that the patient's blood is centrifuged, the plasma is separated from the blood clot, the isolated clot is homogenized, colloidal nanostructured silver, nickelide powder and the plasma obtained after centrifugation are added to it, then the components are mixed using ultrasound and a homogeneous composition is obtained green color with a pearly overflow, which is used for 1-2 hours (RF No. 2399387).

Known composition for stimulating the regeneration of the bone tissue of the jaws, containing calcium hydroxide, barium sulfate and nanocrystalline cerium dioxide in isotonic solution. The ratio of components in the composition is 40-42 wt. % calcium hydroxide; not less than 8 wt. % barium sulfate; 0.3-2 wt. % nanocrystalline cerium dioxide; the rest up to 100 wt. % - isotonic solution (RF No. 2653480).

A known method of dental implantation, which consists in the following steps. An incision is made in the mucous membrane and periosteum. The alveolar process of the jaw is exposed. Form a bone bed. The resulting bone canal is filled with autoplasma in the form of a gel enriched with platelets, after which the implant is installed by instrumental screwing. Before suturing, a membrane of autoplasma enriched with platelets is placed on the alveolar process. The disadvantage of this method is the lack of primary stability of the intraosseous part, narrow indications for use, insufficient osteoinductive potential, delayed integration with bone tissue, and high trauma. (RF No. 2416376).

There is a known method for improving the reliability of dental implantation at low bone density, which consists in making an incision in the mucous membrane and periosteum, exposing the alveolar process of the jaw, forming a bone bed, the resulting bone channel is filled with autoplasma in the form of a platelet-rich gel, after which the implant is installed using the instrumental method. screwing, before suturing on the alveolar ridge, a membrane is laid from autoplasma enriched with platelets (RF No. 2435547). This method does not provide for the possibility of increasing the volume of the bone and, therefore, is applicable only in clinical situations that do not require the restoration of atrophy of the jawbone.

A known method of regeneration of a bone defect, including detachment of the mucoperiosteal flap, preparation of the internal surfaces of the bone bed with the help of a bone-replacing material until complete fit, filling the defect with autoplasma enriched with platelets and growth factors, covering with a resorbable collagen membrane, reducing the edges of wounds and suturing. As a bone substitute material, a crushed resorbable collagen membrane Bio-Gide is used, previously combined with a thrombin solution 50 U/ml until thickening in an amount of 1-5 wt. %, after which the inner surface of the bone defect is closed with the resulting mixture by compaction, the prepared inner area of the defect is filled with platelet-enriched autoplasma of the patient containing nanodispersed cerium dioxide and Renoplastin, then the Bio-Gide resorbable collagen membrane cut in shape and size is placed inside the defect, ensuring its complete adherence to autoplasma, after which a Bio-Gide resorbable collagen membrane is placed on the edges of the bone defect with a porous surface inward, overlapping the edges of the defect by 3-4 mm under the mucous membrane, and a second resorbable collagen membrane Bio-Gide is additionally placed on top with a porous surface outward crosswise for tight fixation bone defect (RF №2709723).

A biocomplex is known for stimulating the restoration of the microarchitectonics of the bone tissue of the maxillofacial region, containing platelet-enriched autoplasma of the patient, a nanostructured biostimulator, a filler and an activator Renamplastin, and nanocrystalline cerium dioxide is used as a nanostructured biostimulator, in the following ratio, wt. %: platelet-rich autoplasma - 5-50; nanocrystalline cerium dioxide - 1-5; activator - 1-10; isotonic solution - the rest is up to 100%. The biocomplex is applied in the form of a gel. Nanocrystalline cerium dioxide is dissolved in an isotonic solution. EFFECT: invention provides reduction of the time for restoring the integrity of bone structures by optimizing reparative osteogenesis, as well as increasing the convenience of using the biocomplex by creating a composition in the form of a gel that is convenient for use (RF No. 2726821).

Common disadvantages of the known compositions and methods are: - the absence of any carrier, for example, in the form of granules, osteoplastic materials, membranes, etc. does not allow to fully give volume (shape) to the filler, which will subsequently lead to its spreading and diffusion into the surrounding tissues, as a result of which the expected positive result of bone growth is not fully achieved;

- high risk of complications in the donor area;

- long term treatment and the onset of a useful result.

The technical objective of the invention is to create a bioengineering composition for filling a bone defect in a plastic form based on L-PRF and PRP-plasma enriched with platelets and growth factors, using nanodispersed cerium dioxide and granular filler.

The technical result of using the proposed bioengineering composition is the creation of a plastic bioresorbable composition that has a directed stimulating effect that affects the proliferation of osteoblasts, reduces atrophic processes, preserves the structure of the mucous membrane, minimizes inflammatory complications in the postoperative period, and achieves more reliable isolation of the bone wound from negative impacts. oral contents, including pathogenic infection.

The technical result is achieved through the use of a plastic bioengineering composition to replenish the volume of the bone tissue of the maxillofacial region, including a mixture of granular xenogenic or synthetic filler with a fibrin clot L-PRF with a particle size of 0.25-1.00 mm and a suspension of PRP with patient plasma with nanodispersed cerium dioxide in physiological solution at a concentration of 10 ^-5 M at a ratio of 2:1 at a ratio of components of the composition filler (g) : L-PRF (g) : PRP with nanodispersed cerium dioxide (ml) equal to 1:4:2.

The presence in the composition of nanosized cerium dioxide dissolved in the patient's PRP-enriched plasma provides improved cell proliferation, antibacterial and antiviral effects, and a significant improvement in the therapeutic effect. Nanodispersed cerium dioxide is a unique inorganic material exhibiting a high degree of oxygen nonstoichiometry in the nanocrystalline state.

The specific ability of nanosized cerium dioxide to regenerate is an important property of this material. Traditional antioxidants (ascorbic acid, tocopherol, methionine, etc.) are able to participate in only one redox cycle, after which they are inactivated. Nanodispersed cerium dioxide has an advantage over existing antioxidants, and in some cases surpasses them in its activity.

The essence of the invention is illustrated by the following examples of the implementation of the proposed methods.

EXAMPLE 1. Method for obtaining a plastic bioengineering composition. See table 1

In patients from the cubital vein, venous blood was taken according to the standard method in three test tubes in a volume of 9 ml each - two of them without an activator to obtain PRF clots and one with an activator sodium citrate to obtain PRP plasma. Immediately after blood sampling, the tubes were placed in a centrifuge. To obtain fibrin (L-PRJ) clots, tubes without an activator were centrifuged in a given mode: 2700 rpm for 12 minutes. After that, three layers were formed in the tubes - blood plasma, platelets and leukocytes in the structure of a fibrin clot, and erythrocytes deposited at the bottom of the tube. Then, a fibrin clot rich in leukocytes and platelets was taken from the test tubes using straight tweezers and placed in a sterile cup. The resulting plasma clots were squeezed out in a box to remove excess serum. Fibrin clot (L-PRF) was crushed and mixed with a granular filler (granule size 0.25-1.00 mm), which was used as xenogenic or synthetic osteoplastic material. Materials used to replace bone defects:

- xenogenic - obtained from purified bone meal of cows and pigs;

- synthetic - artificial hydroxyapatite.

The tube with sodium citrate activator was centrifuged at 10,000 rpm for 10 min to obtain PRP plasma, which was then withdrawn with a syringe into a separate tube in a volume of about 5 ml. To this PRP plasma was added a suspension of nanodispersed cerium dioxide in saline with a particle diameter of 5-10 nm at a concentration of 10 ^-5 M in a volume of 2.5 ml, in a ratio of 2:1.

The filler, crushed fibrin clots (L-PRF) were placed in a rectangular titanium saucer 12×17×8 mm in size. Then, 2 ml of a plastic material of nanodispersed cerium dioxide was added in a liquid dispersion medium of blood plasma PRP-plasma obtained from a test tube with an activator.

In a titanium saucer, a composition was obtained from an osteoplastic material as a filler, crushed fibrin clots (L-PRF) and the resulting plasma with nanodispersed cerium dioxide. Then, 2 ml of a suspension of nanodispersed cerium dioxide in a liquid dispersion medium of blood plasma PRP-plasma obtained from a test tube with an activator was added. The ratio of components (filler : PRF : PRP with nanodispersed cerium dioxide) is 1:4:2.

The composition was stirred for 5-10 seconds with a titanium spatula until a homogenized mixture was obtained. Within 10 min, the filler was saturated with the solution, absorbing it into itself. The resulting composition was taken out of the mold and placed on a fine grid. The rest of the liquid comes out and a soft plastic bioengineered composition is obtained, which can be used to fill bone tissue defects of various configurations. The composition completely fills the defect, which will allow maintaining the volume of bone tissue until new bone is formed, and growth factors and nanodispersed cerium dioxide, which promotes stimulation of bone regeneration with the formation of the correct morphogenetic bone.

In all cases of testing, a decrease in atrophic processes was observed, and the structure of bone tissue was preserved. No inflammatory complications were noted in the postoperative period.

This biocomposition for filling bone defects in the maxillofacial region has a directed stimulating effect that affects the proliferation of osteoblasts, as well as a pronounced biostimulating effect.

The results of using the biocomposition, see table 1. Example 2. Biological tests (see Fig. 1 and Fig. 2).

The experiments were carried out on chinchilla rabbits. On the right side of the rabbit jaw in the diastema between the incisors and molars, a new biocomposition was introduced into the prepared hole to replenish the volume of the jaw bone tissue and stimulate regeneration based on xenogenic bone filler, L-PRF and PRP with nanodispersed cerium dioxide, and bone granules of the material were injected on the left side Bio Oss.

To obtain reliable data, a complex morphological analysis was carried out at the stages of bone tissue regeneration, taking animals out of the experiment on days 15, 25, 35, 45, and 55. Morphological analysis showed that after implantation of the Bio-Oss granular material, by day 35, a larger connective tissue focus with basophilic masses and small fragments of necrotic bone beams is formed, and by day 55, newly formed bone tissue is formed, similar in structure to the compact bone of the cortical plate (Fig. 1).

At the site of implantation of the new proposed bioconstruct, by day 35, the volume of the newly formed connective tissue is much less, bone sequesters and basophilic material are not found. The processes of osteosynthesis and remodeling of the bone tissue are not completed by the 55th day, bone sections are formed that are similar in structure to both compact and cancellous bone tissue (Fig. 2).

The problem was solved through an integrated approach to creating a permanent osteoinductance in the area of a bone defect using osteoplastic materials containing growth and regeneration factors of bone tissue, which are in direct contact with the growing bone tissue. The use of a new composition based on a filler of various origins with platelet-enriched autoplasma makes it possible to create a high concentration of growth factors in the site of its introduction into tissues, which control local processes of regeneration and immunocorrection.

Claims (1)

Plastic bioengineering composition for replenishing the volume of bone tissue in the maxillofacial region, including a mixture of granular xenogenic or synthetic filler with a fibrin clot L-PRF with a particle size of 0.25-1.00 mm and a suspension of PRP from the patient's plasma with nanodispersed cerium dioxide in saline at a concentration of 10 ^-5 M at a ratio of 2:1 at a ratio of components of the composition filler (g) : L-PRF (g) : PRP with nanodispersed cerium dioxide (ml) equal to 1:4:2.

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