RU2477996C1 - Medical adhesive bioimplant of new generation of biopolymer nanocomposites in form of semi-synthetic polymer matrix with use of laser processing - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is described is a medical semi-synthetic adhesive bioimplant of new generation of biopolymer nanocomposites in the form of semi-synthetic polymer matrix containing a base in the form of low-molecular polyisobutylene, an excipient in the form of collapan, a binding agent in the form of castor air-oil mist lubrication; in order to improve setting of the microporous adhesive sandwich, a repetitively-pulsed laser scalpel (CO₂ laser) is used intraoperatively. An upper layer hardener is a polymer adhesive strip with polyacrylamide hydrogel placed in a polymer bath.

EFFECT: medical semi-synthetic adhesive bioimplant has high adhesion characteristics.

Description

The invention relates to medicine, and more specifically to traumatology, orthopedics, implantology, neurosurgery, maxillofacial surgery, reconstructive plastic surgery, and can be used as an adhesive additive (bioimplant). The closest analogues: cl. C1 20031220, RU, patent No. 2218895, class. A 20030319, CN, application No. 1403168. This adhesive bioimplant does not violate the natural biofield of the human body and is hypoallergenic in structure.

At the current level of development of surgical technique, materials with high osteogenic potential, capable of rapid restoration and replacement of bone tissue are required. The materials created having pronounced osteoinductive and osteoconductive properties should be convenient for the clinical application of consistency, which would allow the surgeon to fill in the defect zones of various configurations, are easy to obtain, and, as a result, are constantly available.

The aim of the invention is the creation of a new generation of semi-synthetic medical adhesive bioimplant based on biopolymer nanocomposites in the form of a semi-synthetic polymer matrix, which is non-toxic and biodegradable, the composition of which corresponds to the composition of the extracellular matrix of bone tissue in combination with osteoinductive and osteoconductive properties. The surgical adhesive according to the mechanism of action is a glue-sealant with biological inclusions that allow filling zones of bone defects of various configurations.

This invention involves the impact on the solution of one of the pressing health problems - the restoration and replacement of damaged mineralized tissues. In surgical practice, it is necessary to replace bone defects and cavities that arise in the treatment of a number of diseases associated with bone pathology.

It is known that pathological changes in bone tissue often require filling a bone defect with a substance that can stimulate reparative processes to eliminate them.

In this regard, it is proposed to create a biologically active polymer composite material, which in its strength characteristics and composition would be as close to bone tissue as possible.

It is known that the bulk of fractures, in particular the femoral neck, occurs in older people, which exacerbates their condition, and patients often die from congestive pneumonia. At the moment, in medical practice, to eliminate the consequences of fractures, various application of screws, knitting needles is used, which lengthen the time of the operation and lead to additional surgical intervention subsequently (removal of needles, plates, etc.). The presence in the body of any metal objects, from the point of view of oncologists, is undesirable, because they accumulate external energy and ultimately cause the development of oncological processes. In connection with the foregoing, a need arose to develop new methods for fixing bone fragments. One of the less traumatic and effective methods of fixing bone fragments is the creation of bone glue, which could return the patient to an active standing position.

The main criterion for the obtained adhesive is its high adhesive characteristics, the curing time of the adhesive composition is on average 2-3 minutes, after which there is a rigid fixation of bone fragments. The entire procedure for applying, heating and drying the glue is an average of 3-5 minutes. In the process of osseointegration, glue undergoes further biodegradation for 6-8 months. Moreover, the time from the start of mixing until the moment the biopolymer nanocomposite is poured into the syringe should not exceed 60 seconds. The filled syringe must be kept for 1-2 minutes, so that during this time air bubbles can stand out and the biopolymer nanocomposite reaches the optimal consistency.

With high adhesion and fast fixation of bone fragments with an adhesive bioimplant, the patient's rehabilitation time (placing on crutches) with a gradual increase in the load on the injured area (leg) can be several days after the operation. Moreover, it is planned to give the patient a load on the operated leg without crutches within a month. the glue is biodegradable, and there are no staples or other metal objects.

The most common fractures of the lower jaw are the neck of the articular process, the angle of the jaw in the area of the canines and the median fracture. Moreover, it is not always possible to completely fix bone fragments with the help of metal wire and screws, in these cases glue is used.

To accelerate the setting of the glue during the operation, a laser scalpel is used, operating in a pulsed-periodic mode (CO ₂ laser).

Surgical devices of the type (lancet), YAG / CO ₂ Sharplan are used, operating both in continuous and in pulsed mode with a modulation frequency of up to 50 MHz. A wavelength of 10.6 microns with an output power of up to 50 watts. The duration of the radiation pulse in a pulse-periodic mode (adjustable) is 50000-150000 cut-offs per second (50000 / sec), (150000 / sec), spot diameter: 0.3 mm. The duration of the pause between pulses is 0.05-1.0 s. There is a built-in cooling system that is controlled automatically, air-liquid type, placement in the operating room - floor or wall. An helium-neon laser of the LGN-221 type, emitting in the visible part of the spectrum (= 0.64 microns) with an output power of up to 1 mW (R. Bagramov, M. Aleksandrov, serves as an indicator of the presence of invisible infrared CO ₂ laser radiation in the setup). Y. Sergeev, Lasers in dentistry, maxillofacial and reconstructive plastic surgery).

This technique is applicable both in general traumatology, surgery, reconstructive plastic surgery, and in maxillary surgery.

As a rule, the adhesive sets for a very long time, 30-40 minutes, which is unacceptable in the operation. Therefore, in this invention uses an accelerated method of heating with a laser scalpel.

The glue is obtained by flat-slit extrusion, the adhesive tape in shape resembles a wide adhesive plaster from 0.5 cm to 2-3 cm in diameter, depending on which bone to work on. After the operation, the adhesive patch is applied to the fracture line after drying the fracture line in the laser scalpel, so that the adhesive ability of the bones is better. Then, with the same laser scalpel in the 2-3 W mode, the entire surface of the glue is heated. Moreover, all types of fractures of any area are also fixed by this glue.

The technical result is achieved by the fact that in the present invention, modern biologically active polymeric materials with a mineral polymer binder are used as a basis. This combination gives an increase in biocompatibility, physico-mechanical properties and osseointegration. Further grinding and the creation of nanolayers contributes to the persistent adhesive factor.

The experimental part on rabbits was carried out in the research laboratory of 1 MGMU them. Sechenova, in order to analyze the reparative processes in the jaw under the influence of biopolymer nanocomposites of medical glue-bioimplant based on a semisynthetic polymer matrix, physicochemical, physicomechanical, biomechanical tests of the biopolymer nanocomposite was carried out by the Centaur Scientific and Commercial Center (NCC Centaur "). All studies were carried out under the supervision of the Association of NGOs "Management Polymer". Given the high demand for osteoplastic materials with pronounced osteoinductive and osteointegrative properties for surgical practice, experimental studies have been carried out to justify the use of new generation biopolymer nanocomposite materials to eliminate the lower jaw bone defect.

Materials and research methods

The experiment was performed on 24 male chinchilla rabbits aged 3.5 to 4 years, having a body weight of 5-5.5 kg. All animals passed the required quarantine observation period (15 days), then were taken for the experiment. The control group consisted of 6 rabbits, the experimental group - 18.

All animals under conduction and infiltration anesthesia with 1% lidocaine solution in the amount of 5-6 ml made an incision in the skin and subcutaneous tissue, enveloping the angle of the lower jaw, the periosteum was exfoliated, the jaw branch was exposed. After this, a bone defect with a diameter of 0.4-0.5 mm was formed with a spherical boron. A similar operation was performed on the opposite side. In animals of the experimental groups, the formed bone defects were filled with a blood clot. Soft tissue was put in place and sutured with silk. In the animals of the experimental groups, the resulting bone defect in the region of the angle of the lower jaw was filled with GAP-99 (hydroxyapatite-99) granules on the right, and collapse granules based on biopolymer nanocomposites on the left.

GAP-99 is a granule with a size of 0.25-2 mm of a round or irregular shape in white, which includes 50% hydroxyapatite and 50% tricalcium phosphate. The drug is the basis of the inorganic matrix of hard tissues, is biocompatible with human tissues, stimulates osteogenesis, promotes the adsorption of its own morphogenetic proteins, is resorbed after filling the bone cavities, is replaced by bone tissue.

Collapan is an osteoplastic material consisting of highly pure hydroxyapatite and specially processed collagen with the introduction of antimicrobial agents. A valve based on biopolymer nanocomposites is a granule with a size of min 0.5 cm3. white, which includes artificial hydroxyapatite, collagen, a drug with an antimicrobial component. Collapan is a bioactive material used to restore bone tissue and prevent purulent complications. The valve is an artificial material, therefore there is no risk of transmission of infectious diseases (AIDS, hepatitis, etc.), as well as immune and gene incompatibility with these biomaterials. Collapan actively stimulates osteogenesis, significantly enhances reparative processes in damaged tissues, is completely replaced by newly formed bone tissue, due to which the treatment time is shortened, and the results are improved. The valve retains antimicrobial activity in the wound for up to 20 days, during which there is a uniform release of the antibiotic in the bone cavity. This makes it possible to stop taking antibiotics in the postoperative period, therefore, the toxic effect of drugs on the liver, kidneys, etc. is eliminated, treatment costs are reduced, and the risk of postoperative complications is reduced. Collapan is a carrier of drugs (lincomycin hydrochloride, gentamicin sulfate, metronidazole, claforan, dioxidine, rifampicin, isoniazid). The presence in the valve of antimicrobial agents of various spectrum of action allows you to choose the type of drug that acts purposefully on the identified pathogen, and significantly increases the effectiveness of treatment. The chemical composition and biological properties of the various forms of release of the valve are not different.

Forms of release of the drug - the drug is available in the form of granules, plates or gel. The choice of a valve in the form of granules, plates or gel is due to the convenience of filling bone defects of various shapes and locations.

The valve does not cause rejection, suppuration, allergic reactions. Contraindication to use is individual intolerance to the antibiotic that is part of the drug.

After 1, 7, 14, 30, 60, and 90 days, one rabbit of the control group (2 bone cavities) and 3 rabbits of the experimental group (6 cavities, 3 HAP-99 and 3 with a valve based on biopolymer nanocomposites). The lower jaw was separated from soft tissues, the bone site where there was a defect was cut out 1 × 1 m in size and kept in a 10% solution of neutral formalin for 2 days. After that, the jaw fragments were decalcified with a hydrochloric acid solution for 48 h, frozen with a chloroethyl solution and embedded in paraffin. Sections of 3-5 μm thick were made from paraffin blocks and micropreparations were prepared, which were stained with hematoxin-eosin and pyrofuxin according to Van Gieson.

Experiment Results

On the first day of the postoperative period, the general condition of the animals corresponded to the severity of the surgery. They were inactive, did not eat well. In subsequent periods, the animals improved, they became active and began to take standard food. During the entire period of observation of animals, the postoperative wound was clean; no cases of suppuration were observed.

As a result of a morphological study of bone tissue in the area of the former bone defect one day after the formation of the defect and filling it with a blood clot (control group), as well as GAP-99 granules and a valve based on biopolymer nanocomposites (experimental group), the following changes were found.

In animals of the control group, the postoperative defect was filled with a homogeneous mass with a dense network of interwoven fibrin filaments, erythrocytes and decaying leukocytes were determined in the parietal areas. The vessels were sharply dilated and full-blooded; Haversian canals located near the defect were filled with loose connective tissue.

A morphological study of the bone tissue of experimental animals revealed mature compact bone tissue with small oval and round cavities (lacunae), where osteocytes, a periosteum (periosteum), consisting of an external fibrous layer and an internal osteogenic layer, are located. Massive necrosis of all tissues with extensive hemorrhages (hematoma formation) was observed at the site of damage.

On the 30th day of observation, the cavity of the lower jaw in the animals of the control group was completely filled with granulation tissue, which was replaced at the periphery of the defect by a connective tissue regenerate containing many blood vessels and cellular elements.

In rabbits of the experimental group, focal inflammatory infiltration, insignificant foci of hemorrhages, smaller in comparison with the previous periods of observation were observed at the site of bone damage; the appearance of more mature connective tissue fibers; pronounced plethora of blood vessels; activation, proliferation of osteoblasts of the periosteum, expansion of bone lacunae, mature connective tissue with vessels with an already formed vascular wall, consisting of endothelial, muscle and adventitious layers, the appearance of foci of cartilage-chondroblasts, the formation of fibro-cartilaginous tissue.

After 60 days of observation in animals of the control group, the bone cavities were filled with cell-fibrous connective tissue. On the periphery of the cavity, bone formation was observed. At the site of bone damage, connective tissue was formed, pronounced plethora of blood vessels and proliferation of periosteum osteoblasts, fibro-cartilaginous and osteoid tissue formed. Van Gieson stain (red color - bone tissue, green color - hydroxyapatite GAP-99).

In the animals of the experimental group, at the site of bone damage, mature connective tissue represented by collagen fibers, pronounced plethora of vessels and proliferation of periosteum osteoblasts were observed, fibro-cartilaginous tissue and osteoid tissue were formed.

When stained according to Van Gieson, the initial tissue was stained red, hydroxyapatite - green. A more intense substitution of hydroxyapatite tissue at the site of damage and diffusion into the surrounding tissue.

On the 90th day of observation in animals of the control group, postoperative bone defects of the lower jaw were completely filled with cell-fibrous connective tissue, in which fibrous structures predominated. The bone defect is completely filled with GAP-99 granules. Van Gieson stain (red color - bone tissue, green color - hydroxyapatite GAP-99). In the peripheral areas of the defect, bone formation processes were observed.

In the course of the experiment, the authors came to the conclusion that a new-generation biopolymer nanocomposites (medical glue-bioimplant) collapse is a highly biocompatible osteotropic material that creates a matrix for the formation of new bone and fibrous tissue by direct biochemical binding; possesses pronounced osteoinductive, osteointegrative and osteoplastic properties, weak antigenicity, highly flexible and easily modeled in the form corresponding to the surface of the jaw, resistant to infection.

Lasers, due to the wide range of their effects, have found worthy application in modern medical practice. Especially effective and visual is their use in surgical practice when high-energy light fluxes are used.

Among the numerous laser surgical devices CO _2, lasers generating IR radiation with a wavelength of 10.6 μm are most widely used in world surgical practice, because reliably established themselves as "laser scalpels". The use of a CO ₂ laser is effective in the treatment of various diseases requiring surgical intervention.

Surgical methods using high-energy laser radiation have been used for about 30 years, when the first laser systems appeared. Already then, having received a good clinical effect, the advantages of laser surgery were noted in comparison with electric and cryosurgery.

New generation carbon dioxide lasers are increasingly satisfying the tasks of treating surgical pathology on an outpatient basis.

The interaction of CO ₂ laser radiation with biological tissues directly depends on the water content in them, which is the main substance of absorption of light quanta. The high water content in the tissues of the body (70-80% of the weight of the organs) explains the fact that the effects are dominated by thermal effects, on the basis of which the use of lasers in surgical practice is based. At a temperature of more than 800 degrees. Int. the tissue site completely burns out, which is expressed in a section. When a laser beam is defocused, tissue evaporates, accompanied by their coagulation (temperature 400 degrees Cel.). With further beam defocusing, tissue sterilization occurs.

A tissue defect that occurs after laser exposure, or a laser wound, has its own characteristics both in the formation and development of reparative processes.

1. A high concentration of light energy provides high accuracy of a non-contact incision of biological tissues with a minimum of traumatization.

2. Superficial thermal tissue necrosis prevents the formation of gross scars and stenosis, and also gives a good cosmetic effect in skin operations.

3. Dosed heating of tissues at the site of laser exposure provides the formation of a coagulation zone, which plays a key role in hemostasis, and also leads to the formation of a laser scab, which serves as a biological barrier that prevents wound infection.

4. Pain in the wound after laser application is less pronounced.

5. Due to the penetration of light quanta into the deep layers, photochemical reactions take place to activate cellular elements, due to which the healing process is accelerated.

A distinctive feature of laser wounds is the early and more active formation of granulation tissue with the development of microvessels, which provides a high level of trophic support for cells. This leads to the early formation of the scar, its remodeling and restoration of the histostructure of the organ.

DETAILED DESCRIPTION OF THE INVENTION

The invention is based on a number of physicochemical and biomechanical dependencies that are consistent with empirical analysis and experimental results.

Bone is a mineral organic composite material, the main components of which are collagen (20%), calcium phosphate (69%) and water (9%). The bone is very heterogeneous in macrostructure and mechanical properties. The mechanical properties are determined by porosity (pore content varies from 5 to 95%), the degree of mineralization and the orientation of the collagen fibers. Cortical bone is a composite material, at the nanostructured level, which is an interpenetrating framework consisting of minerals based on HA and collagen fibers. This framework forms a layered microstructure, which, in turn, is basic for oriented cylindrical formations at the macro level. Such a complex structure leads to high strength and, especially, resistance to destruction of bone tissue in accordance with the well-known concepts of the mechanics of the destruction of composite materials with brittle matrices. The main hardening mechanisms responsible for the slow fracture resistance are likely to be deviations of the crack from the interface and elongation of collagen fibers. Bone destruction occurs with deformations of more than 3%. Bone stiffness increases with increasing mineral content.

Calcium phosphate is presented as crystallized or partially crystallized hydroxyapatite or amorphous calcium phosphate (HA), providing bone rigidity. The ratio between amorphous and crystalline structure in bone tissue is a variable and is determined by many factors, including age-related ones. It is known that at the same mineral density of bone tissue with a mineral matrix, the difference in the ratio of HA and ROS content can reach 28%. The formation of crystalline structures from amorphous occurs gradually. Each newly formed mineral since the appearance of the mineral core (a thin layer of calcium phosphate located between the collagen fibrils) has been slowly growing, reaching a thickness of approximately 3 mm, which corresponds to the maximum size of the interfibrillar gap. The transition from the amorphous phase to the crystalline phase takes time, and at the same time, the ratio of the chemical elements that make up the mineral, including calcium and phosphorus, changes. Orthophosphates are bioactive and bioabsorbable materials. However, the possibilities of direct implantation of a structure made of bioactive ceramic material for reconstruction of an organ with damaged bone tissue are very limited (ORTHOSS, Sulcem 1,3; Kryptonite). The reason is the low rates of mechanical strength, including fatigue, and crack resistance of bioceramics, bio-glasses and bio-metals based on calcium orthophosphates, which are significantly 10-100 times lower than that of natural bone tissue.

Of particular importance is the mismatch of the modular elasticity of ceramics and bone tissue. For the normal functioning of the bones of the musculoskeletal system, physiological loads are necessary, the screening of which with a material with a higher modulus of elasticity (ceramics) can lead to degradation of bone tissue. Therefore, ceramic implants can be used only for organs that do not carry significant physiological loads, and with a certain degree of risk. In this case, it is necessary to take into account the influence of the body environment, accelerating the processes of material destruction, dissociative chemisorption and other mechanisms of the so-called "stress corrosion".

A key moment for the development of technology is the creation of material that must meet certain requirements. In addition to the fact that the material must be biocompatible and biodegradable, possessing the specified kinetics of bioresorption in the body and gradually being replaced by bone tissue, it must also be sufficiently technological so that the implant design that is required in shape, size and structure can be made of the material. Of course, the material must be strong enough so that the body can withstand without destroying physiological loads during the transition period. The bioimplant used on the basis of this type of polymer (polyisobutylene) does not possess the possible toxicity of its degradation products and is compatible with the process of osteogenesis by the kinetics of resorption. The biopolymer must have a sufficiently large open porosity, the pores must be interconnected to ensure biological flows and large enough to ensure the life of osteoblasts that build bone tissue. It is assumed that the minimum open pore size should be of the order of 150 microns. The biopolymer should be strong enough, able to withstand loads during the process of formation of new bone tissue, and slowly resorbable over time, preserving its structure and properties for at least 2-3 months after the postoperative period of bioimplant implantation, and the rate of biodegradation should correspond to the rate of formation new bone. The biopolymer should actively adsorb protein from blood plasma, for which the presence of thin pores and surface roughness (the use of nanocarbon-fullerene) are desirable.

Such a biopolymer matrix can be impregnated with drugs (in this case, collapol is used) for local and prolonged introduction into surrounding tissues, for example, to suppress infections that can be introduced during manipulation. Hydroxyapatite (HA) - the most resistant to the absorption of extracellular fluids by the body calcium calcium orthophosphate - is the main mineral component of bone tissue, tooth enamel and dentin. GA plays a crucial role in many physiological processes that occur in the human body. The oversaturation of body fluids with calcium ions and phosphate ions ensures the occurrence of mineralization processes. Collagen is located inside the bone tissue in the form of microfibers with a diameter of 100 to 2000 nm. It was shown that at the same mineral density of bone tissue with a collagen type mineral binder, the difference in the ratio of the contents of hydroxyapatite (HA) and amorphous calcium phosphate (ROS) can reach 28%.

Each newly formed mineral from the moment of melting of the mineral core (a thin layer of calcium phosphate located between the collagen fibrils) slowly grows, reaching a thickness of approximately 3 nm, which corresponds to the maximum size of the interfibrillar gap. The transition from the amorphous phase to the crystalline phase takes time, and at the same time, the ratio of the chemical elements that make up the mineral, including calcium and phosphorus, changes. Moreover, bone tissue apatite - always calcium - is scarce and contains carbonate groups.

A local increase in the content of phosphates in tissue fluids leads to their mineralization, under the influence of the leading role of alkaline phosphatase in a local increase in the concentration of phosphates. A similar effect is achieved by the removal of phosphoric acid residues from hexose phosphates under its influence. As a result, the proportion of free phosphate ions and calcium ions changes, which stimulates the formation of mineral structures. The process of bone resorption is carried out by osteoclasts and mononuclear cells, the process of bone formation by osteoblasts. The relationship between resorption and the formation of new bone tissue is regulated by calcium ions, parathyroid hormone, calcitonin, vitamin D metabolites, as well as sex and thyroid hormones, glucocorticoids, growth hormones and insulin, prostaglandins and the corresponding local action of cytoxins. The biological meaning of the bone remodeling phenomenon is to adapt the mechanical properties of the bone to constantly changing environmental conditions.

It is known that the compressive strength of the spongy substance from the proximal tibia is only about 3.5 MPa, the strength of this substance from the head of the hip joint is 1-15 MPa, the cortical bone strength of the upper joint surface of the tibia is 3-23 MPa. According to some estimates, the strength of the cortical bone can reach 150 MPa. The closest to natural tissue and promising for practical applications is dicalcium phosphate dihydrate (DCPD), precipitated hydroxyapatite (OGA) and amorphous calcium phosphate (ROS). The presence of these phosphates is found in bone tissue. OKF is believed to be a precursor to the crystallization of apatite in dental and bone tissues. Amorphous calcium phosphate has a Ca / P ratio corresponding to that of DCPD. However, the kinetics of the ROS dissolution rate in comparison with DCPD significantly limits the possibilities of its use for bone replacement or remineralization of tooth enamel. In the aquatic environment, ROS passes into calcium - into calcium - deficient OHA:

3Ca3 (PO4) 2 * nH2O®Ca9 (PO4) 5 (HPO4) OH + (3n-1) H2O.

Only two calcium orthophosphates, which can be synthesized under physiological conditions, namely, DCDF and OGA, can find practical application as materials for implantation.

An important property of DCDF is that it preferably crystallizes in the form of whiskers, rod-like or plate crystals, the physical engagement or weaving of which gives strength to the solid precipitate.

This fact seems to be very important due to the fact that the strength of materials based on synthesized calcium orthophosphates is not provided by the process of polymerisation of the structure, as in some other phosphate materials. Precipitated hydroxyapatite Ca10-x (HPO4) × (PO4) 6-x (OH) 2-x is a very complex chemically and structurally compound with a wide homogeneity region (Ca / P from 1.50 to 1.67).

Perhaps the most important property of calcium orthophosphates is their solubility in aqueous media, which determines their in vivo behavior in the human body. The mineral phases of the natural bone tissue of dentin and enamel, characterized by isomorphic substitution, contain significant amounts of biologically important elements: fluorine, chlorine, magnesium, sodium and anionic groups: carbonate and silicate groups. Anionic and cationic substitutions have a significant effect on the biological behavior of GA. In this regard, the question of isomorphic substitutions in hydroxyapatites seems to be very important.

Chemical analysis data showed only minor changes in the composition of materials; the Ca / P weight ratio varied from 2.11 in the initial powders to 2.18 in biopolymer nanocomposites obtained as a result of the sintering and polymerization in the microwave oven.

Granulation of the powders was carried out from a mixture of liquid and solid phases by agglomeration of the powders, followed by rolling of agglomerates and hardening of the bond between the particles while removing the liquid phase. The granulation process is understood as a combination of physicochemical and physicomechanical processes that ensure the formation of particles of a given size, shape, structure and physical properties. The technology of porous granules from HA based on binders - collagen and castor aerosol lubricant KS-M has been developed. Depending on the size of the granules and the content of the binders, the size and distribution of the pores were varied. So, with granule sizes from 0.2 to 2 mm and a porosity of 60-67%, the average pore radius was approximately 50 and 75 μm, respectively. The influence of technological parameters (collagen concentration, component ratio, slope and rotation speed of the granulator plate) on the parameters of the obtained granules was studied. This technology allows to obtain granules with a size of 20 microns to 5-7 mm with a porosity of 55-70 vol.% And a pore size of 0.1-50 microns. The formation of a system of open interconnected pores and shrinkage of granules.

A bimodal pore size distribution of a biopolymer nanocomposite is desirable (large and thin interpenetrating pores, channel interpenetrating pores must have a diameter of at least 100-135 μm to provide blood access to contact surfaces, as well as germination and fixation of bone tissue. Smaller pores are also necessary. since they contribute to increased protein adsorption and adhesion of osteogenic cells.

Moreover, the strength of the biopolymer gradually increases when the bone grows into the interior of the pore network of the implant. The bending strength for a porous implant filled with 50-60% bone tissue is 40-60 MPa. In our case, the biopolymer is filled with dispersed HA particles. For hardening biopolymers based on oxide HA, dispersed particles, partially stabilized, are introduced into them. A biocomposite can be made by mixing HA powder with a collagen solution and then hardening the mixture under UV radiation. Or by pressing a mixture of GA-collapol at a temperature of 40 degrees int. and a pressure of 200 MPa.

There are certain problems in using ceramics based on calcium phosphates to fill bone defects. It is not easy for ceramic tissues to give the required shape to fill the defect, while ensuring a tight fit of the ceramic implant to the bone tissue, necessary for osseointegration, injectability, formability of the biopolymer nanocomposite, ease of dosing and further manipulation with it for a given period of time, machinability with a dental instrument and, especially mechanical properties.

Precise control of the total porosity of the pore size as well as the internal porosity is required. To date, it has been established that an increase in the specific surface area and porosity of the polymer biocomposite positively affects the kinetics of bone formation and, therefore, improves bioactivity (a set of material properties that allows you to create strong direct contact with living bone), and the biodegradation rate should correspond to the rate of new bone formation, and also possess the required mechanical strength. When applying biopolymer material to the bone substrate with a pulse-periodic laser, the coating thickness is 0.05-5 microns. You can cover crystalline and amorphous structures (forms), and dense and porous biopolymer coatings are formed.

An alternative solution to the problem can be considered the development of a new generation of biopolymer implants with improved formability, the ability to completely fill a defect in situ, a given setting and hardening rate, and the required mechanical properties. Using such materials, many tasks arising in dentistry and bone surgery can be realized. The use of chemical technology, material science and technology of materials based on calcium phosphates and new generation biopolymers, taking into account nano and laser technologies, as well as the results of their biological research, allow us to make very optimistic forecasts about the possibility of a significant breakthrough in solving the problem of bone tissue regeneration using such materials. In particular, the technological characteristics of biopolymer nanocomposites based on HA (collagen fibers) have been improved due to the regulation of porosity and pore size in the biopolymer nanocomposite, in particular, the characteristics of injectability, formability of the biopolymer nanocomposite, ease of dosing and further manipulation with it for a given period of time, processability have been improved dental tool and, especially, mechanical properties. In the case of applying carbon-based nanolayers (cyclohexane derivatives can be taken as the basis), applied by the ion-plasma method to the entire polymer “sandwich” or in layers. Nanolayers are formed as a result of electrification of a film under the influence of particles of a gas-discharge plasma (the possibility of obtaining an analogue of an artificial muscle). Alternative deposition of nanolayers can be carried out by a repetitively pulsed laser, with the thickness of the coating being 0.05-5 microns.

The biopolymer nanoglue composition is a microporous sandwich prepared in a microwave oven from a viscous flow melt with a preheating temperature of about 68 degrees Cel. (the melting point of low molecular weight polyisobutylene), which is applied to the matrix substrate (pre-treated and dried bone surface with 95% ethyl alcohol). For a better grasping of the material, a biopolymer (nano) composite tape (patch) is glued on top, obtained by the method of flat-gap extrusion and carrying out subsequent adhesion by means of a CO ₂ laser scalpel operating in a pulse-periodic mode.

The biopolymer nanoglue composition can be used together with implants, namely: to fill after implant placement, at the osteotomy site, to cover open metal, to increase the diameter of the pre-lingual ridge in which the implant is located. When using implants, any particle size of the used adhesive biopolymer nanocomposite can be used - both coarse-grained and fine-grained. The choice of material depends on the size and importance of the defect.

A biopolymer nanocomposite used in traumatology, orthopedics, implantology and maxillofacial surgery, which includes, as a rule, low molecular weight polyisobutylene with microporous carbon nanoinclusions that contribute to a persistent increase in the adhesion factor. Low molecular weight polyisobutylene is a rubbery product with cold flow.

Polyisobutylene is a viscous, transparent, odorless and tasteless mass. Polyisobutylene is a saturated polymer, highly resistant to oxygen, ozone, a solution of acids, alkalis and salts, withstands the action of strong oxidizing agents, does not contain harmful impurities, and is widely used in the manufacture of adhesives. The experiment uses an osteoplastic material, a valve, consisting of very pure hydroxyapatite and special-processed collagen with the introduction of antimicrobial agents, used to restore bone tissue and prevent purulent complications. Used purified collagen from type 1 bovine skin without cross-linking, as the rate of its degradation depends on the number of cross-links in collagen. Due to its natural origin, the used collagen with hydroxyapatite, which are part of the valve, in its structure completely correspond to the spongy bone.

The high porosity of the structure of the composite biodegradable polymer provides maximum space for ingrowth of endogenous bone. Biomechanical stability provides the process of biological integration. The granular form contributes to convenient use when working with small defects. The biopolymer nanocomposite additionally includes KS-M castor aerosol lubricant, which is chemically inert - the range of operating temperatures (from -40 degrees. Int. To +200 degrees. Int.), And also has a low viscosity dependence on temperature. KS-M has good dielectric properties, has no smell and taste, does not cause negative reactions in humans. In addition, it is economical, convenient and safe to use. There is a sanitary and epidemiological conclusion. The biopolymer nanocomposite also includes a polyacrylamide hydrogel placed in a polymer bath, used to cure the composition (biodegradable polymer tape, in the form of a patch) by flat-gap extrusion.

Polyacrylamide hydrogel and compounds based on it are low toxic and do not have long-term effects on the body. The maximum permissible concentration of polyacrylamide in melts and solutions, taking into account MMP (molecular weight distribution), should not exceed 0.1 μg / L. Polyacrylamide has the ability to biotransformation and biodegradation. Anionic polyacrylamide has no somatic toxicity to aquatic organisms and microorganisms. The polymer molecules are too large to be absorbed in tissues and cells.

Semi-synthetic new generation medical adhesive bio-implant based on biopolymer nanocomposites in the form of a semi-synthetic polymer matrix containing low molecular weight polyisobutylene as a base, a valve as a filler, castor aerosol lubricant as a binder, characterized in that it accelerates the setting of microporous sandwich operation a laser scalpel operating in a repetitively pulsed mode (CO ₂ laser) is used. As the hardener of the upper layer of polymer tape in the form of a patch, a polyacrylamide hydrogel is used, which is placed in a polymer bath in the following ratio of components,%

Low molecular weight polyisobutylene (base) Up to 55 Valve (filler) Up to 35 Castor Aerosol Grease (Binder) 5-15 Polyacrylamide hydrogel (hardener) Up to 5

The results of the experiments showed that this biopolymer nanocomposite for medical use has sufficient strength close to the strength of bone tissue; high fatigue resistance under the influence of static and dynamic loads, especially in a corrosive environment of the body, as well as satisfactory fracture toughness.

Taking into account nanoparticles, the need for biopolymer nanocomposites can be increased several times without increasing production volumes. This is due to the fact that in bone cement the proportion of particles interacting with modifiers is no more than 30%, the remaining 70% act as an inert filler. Using special planetary mills, the proportion of nanoparticles based on nanodispersed modifiers (for example, the presence of nanodispersed particles of castor aerosol lubricant in the composition of a biopolymer nanocomposite), which, in contrast to interacting particles of bone cement, is up to 90%, i.e. to obtain the required biopolymer nanocomposite of the biomaterial, 3 times less is required, replacing two parts of the three initial volumes with filler. Moreover, the introduction of nanodispersed modifiers into biopolymer nanocomposites can significantly increase the strength of biopolymer nanostructures made from them, which exceed the strength of ordinary bone cement by an average of 2.5 times, and the likelihood of fatigue stresses in general is 3 times lower.

This method is also interesting from the point of view that production costs of this kind in some cases are minimized. Such nanomaterials make it possible to modify a biopolymer nanocomposite using fullerene nanoparticles - viscosity bioregulators.

When using implants containing up to 35% of the valve, it was revealed that the bone component of integration is due to direct contact of mineralized bone structures with the surface of the biopolymer nanocomposite.

Claims (2)

1. Medical bio-implant glue, characterized in that it is a biopolymer composite in the form of a semi-synthetic polymer matrix, containing low molecular weight polyisobutylene as a base, a valve as a filler, castor aerosol lubricant as a binder, and polyacrylamide as a hardener of the upper layer of bio-implant glue hydrogel
in the following ratio of components,%:
Low molecular weight polyisobutylene (base) up to 55 Valve (filler) up to 35 Castor Aerosol Grease (Binder) 5-15 Polyacrylamide hydrogel (hardener) up to 5 2. The medical bioimplant glue according to claim 1, where a laser scalpel operating in a pulsed-periodic mode (CO ₂ laser) is used to accelerate the setting of the glue during surgery.