RU2738406C1 - Method for optimizing reparative osteogenesis - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention refers to medicine, particularly dentistry and maxillofacial surgery, and can be used in operations to increase maxillary bone volume. A method for optimizing reparative osteogenesis involves single use of a bio-antioxidant solution of thiophane based on 2% hyaluronic acid immobilized on Polysorb MP at temperature of 38°C.EFFECT: technical result consists in accelerating the formation of bone regenerate regardless of type of biomaterial (auto-allogenic bone, preparations based on calcium hydroxide, porous titanium), without inflammatory and toxic side effects due to anti-inflammatory and anti-radical activity of the components of the solution.1 cl, 3 ex

Description

The invention relates to medicine, in particular dentistry and maxillofacial surgery, and can be used in operations to increase the volume of the bone tissue of the upper jaw (subantral augmentation, sinus lifting).

From the state of the art, methods are well known for optimizing reparative osteogenesis in surgical methods for increasing the volume of the jaw bone tissue by creating optimal conditions for bone repair in the zone of atrophy of the alveolar process of the upper jaw. This method is subantral augmentation or sinus lifting, when auto- or allogeneic bone, synthetic biomaterials, composites and metals (titanium, for example) are used to increase bone volume, instead of atrophied bone. Regardless of the type of bone substitute, the process of repair and formation of new bone in the areas of atrophy of the maxillary alveolar process proceeds in several stages: catabolism of tissue structures and cell infiltration, cell differentiation, formation of a primary osteon, and regeneration rearrangement, of which the most promising for directed optimization of reparative osteogenesis is the second stage (cell differentiation), lasting from 7 to 14 days. It is at this stage, due to DNA and RNA activation, that the small-cell infiltrate is redirected towards the fibroblastic, chondroid or osteoid diferon. Depending on the chosen direction, differentiation occurs either with the formation of osteoid tissue with complete revascularization of the primary callus (favorable outcome), or by fibrogenesis with cell metaplasia towards the cartilage tissue (unfavorable outcome).

Several methods are known for stimulating reparative regeneration at the stage of cell differentiation.

These include the transplantation of genetically determined osteogenic prodromal cells with a high potential for osteoblastic osteogenesis (Kirilova I.A. Determined bone graft as a stimulator of osteogenesis: modern concepts / I.A. Kirilova // Spine surgery. - 2004. - No. 3. - S. 105-110). With obvious advantages of the technique, expressed in the actual acceleration of reparative osteogenesis, the disadvantages of the method are the high labor intensity of the preparation and cultivation of prodromal cells, as well as a short period of their existence outside the nutrient medium.

Another effective method is the use of growth factors and bone morphogenetic proteins, which have the ability to stimulate the synthesis of bone collagen proteins and optimize the differentiation of their precursors (Bilic R., Simic P., Jelic M. et al. Osteogenic protein-1 (BMP-7 ) accelerates healing of scaphoid non-union with proximal pole sclerosis // Int. Orthop. - 2006. - Vol.30. - P. 128-134).

However, a significant limitation of the use of these methods in clinical practice is the high laboriousness of isolating and purifying growth factors, as well as difficulties in their targeted delivery directly to the bone defect zone (Yamamoto M, Takahashi Y., Tabata Y. Enhanced bone regeneration at a segmental bone defect by controlled ralase of bone morphogenetic protein-2 from a biodegradable hydrogel // Tissue Eng. - 2006. - Vol.12, N5. - P. 1305-1311).

In addition, the deposition of these factors in the required area of the bone is possible only in the presence of carriers (scaffolds) that are capable of adsorbing, and then, for a long period of time sufficient to complete reparative regeneration, to release growth factors and morphogenetic proteins.

Finally, the above methods of potentiating reparative regeneration remain very laborious and expensive, despite the rapid development of cellular and genetic engineering.

The most promising is the wider use of bioantioxidants and stimulants of reparative osteogenesis, since all reparative processes in bone tissue occur under the induction effect of the hormonal system and a group of bioactive substances.

The closest in essence and selected as a prototype is a method for optimizing reparative bone regeneration, based on the use of a bioantioxidant solution of thiophane based on an oil solution of alpha-tocopherol, which has an antioxidant effect and involves the transfer of a hydrogen atom from the alpha-tocopherol molecule to the peroxyl radical with the formation of hydroperoxide ( Method for optimizing reparative bone regeneration, RU 2297217, IPC A61K 31/10).

The objective of the prototype invention is to create optimal conditions for the process of reparative regeneration by preventing infectious complications, detoxifying the body and improving the rheological and antiplatelet properties of blood.

The authors refer to a positive therapeutic effect, which consists in accelerating the restoration of bone integrity and optimizing treatment for combined lesions due to antiradical activity. The technical result is achieved through the use of a synthetic sulfur-containing phenolic bioantioxidant - thiophane.

A method for optimizing reparative osteogenesis according to the prototype consists in the use of a bioantioxidant solution of thiophane based on an oil solution of alpha-tocopherol at the rate of 5 mg of thiophane per 5 ml of alpha-tocopherol, which is injected through a PVC catheter into the bone marrow canal daily, once a day, for four days at a dose of 5 mg / kg body weight, then every other day; the general course of treatment is 10 injections.

The advantages of the prototype: under the action of the claimed bioantioxidant solution, free radical activity decreases, antitoxic and anti-inflammatory properties (due to thiophane) increase, osteogenesis is stimulated (due to alpha-tocopherol).

However, the method for optimizing reparative bone regeneration according to the prototype has a number of disadvantages: the antitoxic effect of thiophane is of a short-term nature, and the stimulation of reparative osteogenesis is carried out only at later stages (despite the declared in the prototype the task of improving reparative regeneration in the early stages) - during the formation of primary osteon and restructuring regenerate, while the most promising stage for directed optimization of reparative osteogenesis is the second stage - cell differentiation, which lasts from 7 to 14 days. In addition, according to the prototype, it is necessary to inject a bioantioxidant solution daily through a PVC catheter, 10 injections per course.

The task is to create optimal conditions for reparative osteogenesis in subantral augmentation by stimulating the differentiation of pluripotent cells for 7-14 days, increasing the level of detoxification and antiradical protection.

The problem was solved by a single use of a bioantioxidant solution of thiophane based on 2% hyaluronic acid immobilized on Polysorb MP at a temperature of 38 ° C.

When solving this problem, a positive therapeutic effect was established, which consists in accelerating the formation of bone regenerate regardless of the type of biomaterial (auto-allogeneic bone, preparations based on calcium hydroxide, porous titanium) used as a matrix and optimization of reparative osteogenesis, proceeding without inflammatory and toxic side effects due to anti-inflammatory and anti-radical activity. The social effect is to improve the quality of life by increasing the service life of orthopedic structures fitted on dental implants installed in the zone of bone tissue atrophy of the upper jaw. The economic effect is to shorten the rehabilitation period for patients.

The specified technical result is achieved through the use of a synthetic sulfur-containing phenolic bioantioxidant - thiophane, hyaluronic acid, immobilized on a universal sorbent - Polysorbe MP.

Thiophane activates regenerative processes at the cellular-membrane level and is an effective inducer of key biotransformation enzymes, contains an aliphatic sulfur atom with a pronounced anti-peroxide activity, not only inactivates free radicals, providing antiradical activity, but also reduces the rate of their formation. Thiophane belongs to non-toxic compounds, does not have a cumulative effect, does not exhibit immunotoxic properties and mutagenic effects.

Hyaluronic acid is an active chondroprotective agent, has a stimulating effect on reparative processes in structures of connective tissue origin, and also helps to inhibit degenerative post-traumatic processes in them. The mechanism of the reparative action of hyaluronic acid is to stimulate the synthesis of glycosaminoglycans and collagen. The use of 2% hyaluronic acid heated to a temperature of 38 ° C, at which its maximum volume is immobilized on the Polysorb MP, has shown itself to be especially effective. The selected temperature parameter was determined empirically, in particular, it was found that hyaluronic acid cooled to temperatures below 38 ° С, for example, to 32-35 ° С, poorly immobilizes on Polysorb MP, forming insoluble flakes, clots and lumps. At temperatures above 38 ° C, for example, at 40-42 ° C, hyaluronic acid loses its osteoinductive properties due to denaturation of bone morphogenetic proteins.

Polysorb MP is an inorganic, non-selective, multifunctional enterosorbent based on highly dispersed silica with particle sizes. The immobilization of hyaluronic acid on the Polysorb MP solves a number of problems, among which the main one is to ensure long-term deposition of synthesized glycosaminoglycans and collagen in the wound, sufficient to stimulate the differentiation of pluripotent cells for 7 to 14 days.

A mixture of thiophane and hyaluronic acid, immobilized on Polysorb MP, in addition to pronounced antiseptic properties, has high sorption, detoxification and antioxidant properties, blocks the aggressive action of free radicals.

Thanks to the reliable deposition of a mixture of thiophane and hyaluronic acid, immobilized on Polysorb MP, a long-term release of biologically active substances is provided even with a single application of the solution.

The method is carried out as follows. A sterile bioantioxidant solution of thiophane is prepared by diluting 10 mg of thiophane in a 2% solution of hyaluronic acid immobilized on Polysorb MP at the rate of 10 mg of thiophane per 20 ml of 2% hyaluronic acid and 10 mg of Polysorb MP, preheated to 38 ° C. The resulting solution at a dose of 0.05 mg / kg of weight is injected with a syringe once into the maxillary sinus during subantral augmentation after placing a biomaterial at the bottom of the sinus (auto-allogeneic bone, preparations based on calcium hydroxide, porous titanium). In the case of using an osteoplastic biomaterial in the form of granules or blocks, it is possible to premix them with a bioantioxidant solution at a dose of 0.05 mg / kg in vitro weight.

The use of the proposed method contributes to the optimization of reparative osteogenesis, the growth of newly formed dense bone with a high concentration of mineral components in the repair, which ultimately contributes to the full osseointegration of the graft (auto-allogeneic) or implant (synthetic biomaterial, metal) with subantral augmentation.

The method has found its application in practical health care, where it has shown high efficiency, which is confirmed by the following clinical examples.

Examples of practical implementation.

Example # 1. Patient C, 44 years old, amb. card No. 3271 filed a complaint about the absence of teeth in the upper jaw on the left. According to the patient, teeth 24, 25, 26, 27 and 28 were previously treated, repeatedly filled, but gradually collapsed and were removed.

Objectively: 24, 25, 26, 27 and 28 teeth are absent, the thickness of the bone tissue of the alveolar process of the upper jaw in the area of the missing teeth 24, 25, 26, 27 and 28 is 4 mm.

Diagnosis: secondary adentia, atrophy of the bone tissue of the alveolar process of the upper jaw in the area of the missing teeth 24, 25, 26, 27 and 28.

Treatment. Under anesthesia with Ultracaini solution 4% - 1.8 ml with adrenaline 1: 100000, an incision was made along the crest of the alveolar ridge and two vertical incisions in the area of the canine fossa and the tubercle of the upper jaw. A complete muco-periosteal flap was detached with a raspor. A piezo scalpel in the anterior wall of the maxillary sinus formed an access in the form of a bony window with a diameter of 2 cm. The mucous membrane of the sinus (Schweier's membrane) is detached from the lower bay of the maxillary sinus and is mobilized.

4 dental implants "Nobel" (Switzerland) are installed in the formed space. Easy Graft® Cryctal granules were inserted between the installed implants and the sinus mucosa as a resorbable two-phase mixture of 60% calcium hydroxyapatite (HAP) and 40% (3-tricalcium phosphate (TCP), with the Bio Linker granule adhesion activator. The mixture was introduced without compaction in bulk) sufficient to fully cover 3 dental implants.

After placing the biomaterial at the bottom of the sinus, a sterile bioantioxidant solution of thiophane was prepared by diluting 10 mg of thiophane in a 2% solution of hyaluronic acid preheated to 38 ° C, immobilized on Polysorb MP at the rate of 10 mg of thiophane per 20 ml of 2% hyaluronic acid and 10 mg of Polysorb MP ...

The resulting solution at a dose of 0.05 mg / kg of body weight through the bone window was injected once into the maxillary sinus with a syringe, where it is evenly distributed in the mixture of biomaterial, laid along the bottom of the sinus. The wound was sutured with interrupted sutures.

The patient's condition after the operation is satisfactory, there is no edema or inflammatory reaction. According to the saccharin test, mucociliary clearance into the nasal cavity is 3 points. Further, the postoperative period proceeded smoothly, which indicates a high level of detoxification and antiradical protection, the stability of the installed dental implants is high.

After 3 months, permanent ceramic prostheses were installed on implants. On the control X-ray taken 1 and 3 months after the operation, complete osseointegration of the implants with the newly formed bone tissue is noted. The condition of the soft tissues in the area of the implants is satisfactory. With the help of plain radiography (orthopantomogram), performed 6 months later, the density of native and newly formed bone tissue and the degree of its integration with the implant surface were assessed. The density of bone tissue in the implantation zone was, on average, from 850 to 1070 units on the Hounsfield scale, which corresponds to the bone type D2-D3. There is no bone atrophy in the area of the installed implants.

Example # 2. Patient K., 47 years old, amb. card No. 6439 complained about the absence of several teeth in the upper jaw on the right, refused the proposed partial removable denture.

Objectively. On the plain x-ray there are no 15, 16, 17 and 18 teeth of the upper jaw, the thickness of the bone tissue of the alveolar process of the upper jaw in the area of the missing teeth is from 1.5 to 3 mm.

Diagnosis: secondary adentia, atrophy of the bone tissue of the alveolar process of the upper jaw in the area of the missing teeth 15, 16, 17 and 18.

Operation. Under infiltration anesthesia with Ultracaini 4% solution with 1: 100,000 adrenaline, subantral augmentation was performed using an autologous bone taken from the chin region. The resulting autograft was ground in a bone mill. Installed 3 dental implants INDURE (USA). After placing the bone autograft at the bottom of the sinus, a sterile bioantioxidant solution of thiophane was prepared by diluting 10 mg of thiophane in a 2% solution of hyaluronic acid preheated to 38 ° C, immobilized on Polysorb MP at the rate of 10 mg of thiophane per 20 ml of 2% hyaluronic acid and 10 mg of Polysorb MP.

The resulting solution at a dose of 0.05 mg / kg of body weight through the bone window was injected once into the maxillary sinus with a syringe, where it is evenly distributed over the autograft laid along the sinus floor. The wound was sutured with interrupted sutures.

The early postoperative period was uneventful, which indicates an increased level of detoxification and antiradical protection, the stability of the installed dental implants is high.

Immediately after the operation, temporary crowns were made and installed, after 2 months - permanent crowns. On a plain X-ray taken 3, 6 months and 1 year after the operation, bone atrophy in the area of the implants is not detected. The density of bone tissue in the implantation area is high and averages 850 to 1000 units on the Hounsfield scale, which corresponds to the bone type D2-D3.

Example No. 3. According to the prototype method. Patient Ch., 49 years old, amb. card No. 7094 complained about the absence of teeth in the upper jaw on the left.

Objectively: on the survey orthopantomogram, there are no 24, 25, 26 and 27 teeth of the upper jaw, the thickness of the bone tissue of the alveolar process of the upper jaw in the area of missing teeth is less than 3 mm.

Diagnosis: partial secondary adentia, atrophy of the bone tissue of the alveolar process of the upper jaw in the area of the missing teeth 24, 25, 26 and 27.

Treatment. Under infiltration anesthesia with Ultracaini 4% solution with 1: 100,000 adrenaline, subantral augmentation was performed using autogenous bone obtained from the mandibular ramus and ground in a bone mill. Installed 3 screw dental implants Astra Tech (Sweden). To stimulate reparative osteogenesis according to the prototype technique, a biooxidant solution of thiophane was made based on an oily solution of alpha-tocopherol at the rate of 5 mg of thiophane per 5 ml of alpha-tocopherol, which was injected through a PVC catheter into the maxillary sinus daily, once a day, for four days in dose of 5 mg / kg body weight, then every other day; the general course of treatment was 10 injections.

The early postoperative period (1-3 days after the operation) in patient Ch. Was complicated by an inflammatory reaction (fever, hyperemia, purulent discharge from the wound through the perforation window in the anterior wall of the maxillary sinus), which indicates a low level of detoxification and antiradical protection. The wound was drained, purulent discharge in a volume of up to 20 ml was obtained, the patient received a course of antibiotic therapy with azithromycin at a dose of 500 mg / day for 5 days.

Due to the complicated course of reparative osteogenesis in the maxillary sinus region and the lack of stability, the dental implants were removed.

On the plain X-ray taken 6 and 12 months after the operation, a slight increase in the volume of bone tissue in the operated area of the sinus by 1-3 mm is determined. The density of bone tissue in the area of operation is on average from 350 to 450 units on the Hounsfield scale, which corresponds to the type of bone D4.

2 years after the operation of subantral augmentation, the patient underwent repeated installation of 3 dental implants. Already in the early postoperative period (up to 3 weeks), the mobility of the implants was found, which did not allow starting the direct prosthetics of the patient. After another 2 years, the phenomena of peri-implantitis were found in the area of the installed implants, which required additional surgical intervention with the replacement of osteoplastic material and repeated prosthetics 1 year after the second operation.

In total, 45 patients were operated on using the developed method over 5 years, 68 dental implants were installed. In all cases of using the proposed method for optimizing reparative osteogenesis, accelerated bone formation was noted, the formation of bone regenerate occurred without pronounced inflammatory manifestations, which indicates an increase in the level of detoxification and antiradical protection and positively characterizes the entire osseointegration process. In the long-term period (2-3 years), no complications in the form of peri-implantitis were observed. The effectiveness of the treatment method was 100%.

According to the prototype method, 17 patients were operated on, 34 implants were installed, of which 15 installed implants were removed due to complications in the form of peri-implantitis, destruction of bone tissue in the implantation area and loss of primary stability. The effectiveness of the method of treatment according to the prototype method was 55.9%.

Thus, the data obtained in a clinical setting confirm the high efficiency of the developed method for optimizing reparative osteogenesis, which makes it possible to form bone regenerate in a relatively short time with a minimum number of postoperative complications with the simultaneous installation of dental implants, which may serve as a basis for the widespread introduction of this method into practice.

Claims (1)

A method for optimizing reparative osteogenesis, including the use of a bioantioxidant solution of thiophane, characterized in that 2% hyaluronic acid heated to 38 ° C is used as the base of the solution, immobilized on Polysorb MP at the rate of 10 mg of thiophane per 20 ml of hyaluronic acid and 10 mg of Polysorb MP, which is injected once into the maxillary sinus at a dose of 0.05 mg / kg of body weight.